Week of Mar 18th 2018 | FDA Sent These Warning Letters to Device & Pharma Companies

FDA posted 7 warning letters this week. Among those we cover:

  • 1 to an API firm
  • 2 to finish pharmaceutical manufacturers
  • 1 to a device manufacturer

We cover these below. The warning letters issued to drug firms all have significant requirements associated with them that firms are to address. We include these requirements because they provide a roadmap of expectations that firms might follow if they self-identify similar shortcomings (even if not so severe).


  • Vilex in Tennessee, Inc. (McMinnville, TN) received a warning letter on January 9th 2018 based on the outcome of an inspection ending April 25th 2017. The firm is a specification developer and relabeler/repacker who conducts limited manufacturing operations for Class I and II orthopedic implants and tools. Deficiencies include but are not limited to:
    • Design history files for eight specific products were not adequate.
    • Design verification and validation procedures are not adequate and are not adequately implemented.
    • Purchasing procedures are not adequate to ensure that suppliers and vendors can meet specified requirements. The firm qualifies suppliers of critical processes based solely on ISO certifications and does not adequately document that firms can meet specified requirements.
    • Risk assessment documentation is not adequate. The firm was unable to identify what the RPN is compared to and whether risk mitigation is necessary.
    • Failure to document rework and reevaluation activities in a device history record.

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  • Malladi Drugs & Pharmaceuticals Limited (India) received a warning letter on March 9th 2018 based on the outcome of an inspection ending September 8th 2017. The firm was placed on import alert 66-40 on December 13th 2017. The 6-page form 483 is available for purchase at the FDAzilla STORE. FDA recommends the firm hire a consultant who can help them come into CGMP compliance. The firm manufactures APIs. Deficiencies include but are not limited to:
    • Parts of the facility are open to the outdoors and the investigator observed birds and insects in the facility near open equipment. FDA asks the firm to conduct a risk assessment addressing this possible contamination for all drugs within their re-test date manufactured and distributed in the US.
    • Vessels used in manufacturing are not constructed of appropriate materials (the warning letter is quite redacted), and these vessels are kept partially full of water for extended times which increases the risk of product contamination. Also, the vessels are not easy to clean. The FDA asks the firm to:
      • “Commit to replacing your unacceptable (b)(4) equipment with equipment composed of materials that are suitable for their intended use.
      • Provide a risk assessment for any drugs within their re-test date manufactured using inappropriate equipment and distributed within the United States. Determine whether any of your equipment surfaces are reactive, absorptive, or additive so that drug quality, purity, or safety may be affected.”
    • The firm has not validated the manufacturing process and does not have adequate on-going controls. For example, twenty-four batches had an OOS result for an unspecified impurity over two years. The firm rejected some batches and reprocessed others. FDA states “Prior to the manufacture of process qualification batches, a manufacturer should identify all significant sources of variability and develop robust controls throughout the operation.” In response to the warning letter, the FDA states that the firm should provide the following:
      • “A data-driven and scientifically sound process validation program that identifies all sources of variability, establishes robust design and controls, and ensures oversight of intra-batch and inter-batch variation on an ongoing basis throughout the product lifecycle. Also, include your process qualification protocol and results from your recent validation study.
      • The results from your stability study of validation batches.
      • A comprehensive, independent evaluation and remediation of your change management system. The evaluation should include, but not be limited to, assuring changes are appropriately justified, approved by your quality unit, and evaluated for effectiveness. Also, include a retrospective assessment of all changes executed outside an appropriate change management process since September 1, 2015, and the effect on product quality.
      • A comprehensive, independent evaluation and remediation of your CAPA system. The evaluation should include but not be limited to a retrospective analysis of the effectiveness of all CAPAs since September 1, 2015.
      • An assessment of drug quality risk and toxicity of the (b)(4) Also, provide an updated investigation into the impurity, including the specification established for it and verification that your process improvements (including automation) have been effective.”
  • Labacont Industrial SRL (Santo Domingo, Dominican Republic) received a warning letter on March 9th 2018 based on the outcome of an inspection ending June 9th 2017. The firm appears to be an OTC drug product manufacturer. FDA placed the firm on import alert on February 8th 2018 and recommended they employ a consultant to assist them in coming into GMP compliance. The redaction is thorough, but it appears that the most significant issue may be the production of β-lactam antibiotics [as assumption] and other products in the same facility. The key issue, for me, is the FDA statement “It is profoundly difficult to completely decontaminate a facility of (b)(4) residues…” Deficiencies include but are not limited to:
    • Sharing manufacturing facility with [β-lactams ?] and other drug products which presents an unacceptable risk to the other drug products. The firm is asked to:
      • “Summarize all in-date batches of drug products produced at your facility and distributed in the U.S. market, and perform a thorough risk assessment of the impact of conducting (b)(4) and non-(b)(4) manufacturing operations within the same facility.
      • Outline your proposed market action plan, including customer notifications and recalls, to address all products in the U.S. supply chain at risk for potential (b)(4)
      • Provide your plan to completely and comprehensively separate your facility for the manufacture of (b)(4) Commit to one of the following two options for the facility you have used to manufacture (b)(4).
        • Dedicate the facility to (b)(4) production only. We strongly urge you to dedicate the facility to (b)(4) only production. It is unacceptable to produce any other products in the same physical facility. If you intend to choose this option, provide your timeline for implementation. Also, be advised that it is inappropriate for different classes of (b)(4) to be manufactured in the same facility. Significantly, our inspection found that you are currently producing (b)(4) and non-(b)(4) for other markets within the same facility, rather than in separate dedicated facilities.
        • Fully decontaminate the facility. It is profoundly difficult to completely decontaminate a facility of (b)(4) residues. If you intend to attempt decontamination so that your facility can resume solely non-(b)(4) production, provide a comprehensive decontamination plan for the facility. Also, provide highly-sensitive methods to detect any (b)(4) and (b)(4) residues throughout the facility, and address all potential sources of cross-contamination of (b)(4) into non-(b)(4) drugs. You should not introduce any drug products into the U.S. supply chain until FDA determines that your proposed decontamination plan, methods, and procedures are adequate, thorough, comprehensively implemented, and verified via an FDA inspection.”
    • The firm fails to ensure that complete laboratory data are maintained and reviewed by the Quality Unit. The FDA requests the firm provide the following:
      • “Provide a comprehensive investigation into the inadequacies in data records and reporting for all products manufactured for the U.S. market and within expiry. Identify omissions, alterations, deletions, record destruction, non-contemporaneous record completion, and other deficiencies. In addition, describe all parts of your facility’s operations in which CGMP information is not recorded and maintained. Include a corrective action and preventive action (CAPA) plan to remediate data recording and retention practices throughout your operation.
      • Provide a risk assessment summarizing the affect of incomplete data on assessing laboratory control and product quality.
      • Provide a detailed corrective action plan that describes how you intend to ensure the reliability and completeness of all the data you generate, including analytical and manufacturing data. This should include procedures that detail your documentation, data evaluation, review, retention, and quality oversight practices. Outline how you will assess your corrective actions for effectiveness.
    • The firm has not validated analytical methods used to test API and final product. FDA asks that the firm provide:
      • “Provide an independent assessment of the suitability of your firm’s test methods and adequacy of methods validation (or verification, for compendial methods) performed for all drug products for U.S. supply and raw materials.
      • Provide your plan of action to complete validation (or verification, for compendial methods) for all analytical methods used in association with products that are shipped to the U.S.
      • Provide a comprehensive independent review of your entire laboratory system, and a CAPA plan that ensures full remediation of the laboratory operation. For example, the review of your laboratory system should include, but not be limited to, the suitability of all laboratory equipment, a fully remediated calibration program, staff competencies, supervisory oversight, data systems, and other elements of laboratory control.”
  • Diamond Wipes International (Chino, CA) received a warning letter on March 7th 2018 based on the outcome of an inspection ending May 17th 2017. The firm is identified as a contract manufacturer. FDA mentions that they have been in discussion with the firm about conducting a voluntary recall for those lots manufactured with poor quality water.  The firm is to contact FDA within five days to provide an update regarding these lots and any potential action. The firm received a warning letter in 2016 based on investigator collected labels and labeling for their OTC sunscreen wipe products. Deficiencies include but are not limited to:
    • Water used in manufacturing of drug products is generated by a system that has not been demonstrated to be capable of consistently producing acceptable quality water. Action limits were exceeded 8 times in fourteen months.  The firm also raised the alert and action limits without justification. The FDA provides a narrative description of why this isn’t appropriate or acceptable. FDA requests:
      • “A comprehensive evaluation of the water system design, including a thorough CAPA plan to install and validate a suitable water system.
      • 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 appropriate microbial limits. Regarding the latter, total count limits significantly tighter than your proposed action and alert limits are generally appropriate for topical products.
      • A detailed risk assessment addressing the potential effects of the observed water system failures on the quality of all drug product lots currently in U.S. distribution. Specify actions that you will take in response to the risk assessment, such as customer notifications and product recalls.
      • Your scientific rationale for the microbiological test limits (i.e., total counts, objectionable microbes) for each of your finished drug products, based on their intended use.
      • A CAPA that ensures routine species identification of microbes in your water system.”
    • Two identified drug products (facial wipes and acne treatment pads) significantly exceeded fungal levels in specifications. The batches were released, and the firm did not conduct an investigation. They did, however, perform a second test which passed and, upon these results, the products were released. FDA requests:
      • “A thorough assessment of your overall systems for investigating deviations, atypical events, out-of-specification results, complaints, and failures. For example, your comprehensive CAPA to these systems should include but not be limited to remediation of your handling of out-of-limit microbiological test results.
      • Improved procedures that assure that you promptly review the sources of variation in your operations that may cause errors, deviations, or failures, to detect emerging problems in your operations before they have adverse effects on product quality.
      • A detailed investigation and root cause analysis of the source(s) of microbiological contamination for all test results that exceeded your acceptance criteria, and an associated CAPA plan.
      • A retrospective review of all lots within expiration date to determine if your firm released other lots not conforming to established specifications or appropriate manufacturing standards.” 
    • The firm’s Quality Unit did not review batch records prior to release. This is a repeat observation from 2015. FDA asks the firm to:
      • “A comprehensive assessment of the adequacy of your firm’s manufacturing operations.
      • A retrospective risk assessment of all unexpired lots of drug products to assess whether any were distributed without prior QCU approval and determine whether each lot met all manufacturing standards and product quality specifications.
      • A detailed CAPA plan to ensure full review and final approval of all batch records by the QCU prior to distribution of any lot of drug products.
      • A comprehensive assessment and CAPA for your QCU to ensure it is adequately resourced and given the needed authority 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 QCU duties.”

Learn more about how FDAzilla can help you achieve your quality and inspection preparation goals: get 483sInspector ProfilesEnforcement Analytics, and GMP Regulatory Intelligence. Contact us if you ever have questions at sales@fdazilla.com.

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About the Author

Barbara W. Unger is Govzilla’s Quality Expert and Editor-in-Chief of GMP Regulatory Intelligence.  She formed Unger Consulting, Inc. in December 2014 to provide GMP Quality consulting services to the pharmaceutical and biopharmaceutical industry.  At Amgen, she led the segment of the Corporate GMP Audit group at Amgen focused on API manufacturers, Quality Systems and Computers.  She developed, implemented and maintained the GMP Regulatory Intelligence program for 8 years at Amgen Inc.  This included surveillance, analysis and communication of GMP related legislation, regulations, guidance and industry compliance enforcement trends.  This was an essential service and tool within the Corporate Audit function.

Unger Consulting Inc. | www.ungerconsulting.net | 805.217.9360

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