Week of July 15th 2018 | FDA Sent These Warning Letters to Pharma Companies

FDA posted 6 warning letters this week. Two were issued to firms manufacturing finished pharmaceuticals. We continue to include the follow-up actions that FDA identified for the firm. Both are addressed below.


  • bB BioCHem Laboratories Inc (Santa Ana, CA) received a warning letter on July 3rd 2018 based on the outcome of an inspection ending December 18th 2018. The firm manufactures over the counter drug products. FDA suggests they employ a qualified consultant to help them come into compliance with GMPs. They use a contract laboratory for some of the product testing. Deficiencies include but are not limited to:
    • Batches of drug products were released without testing for identity and strength of the active ingredient. The firm is asked to provide:
      • Appropriate chemical and microbiological batch release specifications for each of your drug products; 
      • A commitment to test each batch to ensure conformance to finished product specifications before a final disposition decision; 
      • All chemical and microbial test methods used to analyze each of your drug products; and
      • A summary of test results obtained from testing retain samples of all drug products within expiry. You should test all appropriate quality attributes including, but not limited to, identity and strength of active ingredients and microbiological quality (total counts and identification of bioburden to detect any objectionable microbes). If your testing for any previously released batch yields an out-of-specification result, indicate the corrective actions you will take, including notifying customers and initiating recalls.
    • Incoming raw materials were not tested for identity or other quality attributes. Further there were no written specifications for raw materials. The firm is asked to provide:
      • The chemical and microbiological quality control specifications you use to approve release of each incoming lot of components for use in manufacturing. 
      • A description of how you will test each component lot for conformity with all appropriate specifications for identity, strength, quality, and purity. If you intend to accept any testing results on your supplier’s COA in lieu of testing each component lot for purity, strength, and quality, specify how you will first establish the reliability and consistency of your supplier’s test results for these attributes through initial validation (followed by periodic re-validation). In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot.
      • A summary of test results obtained from full testing of all components to evaluate the reliability of the COA from each component manufacturer. Include your standard operating procedure (SOP) that describes this COA validation program.
      • A summary of your procedures for qualifying and overseeing the adequacy of contract facilities that test the OTC drug products you manufacture.
      • A comprehensive, independent review of your material system to determine whether all containers, closures, and ingredients from each supplier are adequately qualified and assigned appropriate expiration or retest dates. Also determine whether your controls for incoming material lots are adequate to prevent use of unsuitable containers, closures, and components.
    • The firm does not have a stability program and testing to support expiry dating. They are asked to provide “your plan, with timelines, to develop and implement a complete drug stability program. This plan should also include an assessment of the stability of drug products currently on the U.S. market within expiry.”
    • The firm lacks a quality unit and, thus, does not have written procedures, documentation for basic drug manufacturing operations including change control, complaints, supplier qualification, and recalls. FDA request they provide “a comprehensive assessment and a corrective action and preventive action (CAPA) plan to ensure that you establish an effective quality unit with appropriate authority, responsibilities. Your response should also include a detailed procedure describing your remediated quality unit’s responsibilities. See FDA’s guidance document, Quality Systems Approach to Pharmaceutical CGMP Regulations, for help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations (21 CFR, parts 210 and 211), at https://www.fda.gov/downloads/Drugs/…/Guidances/UCM070337.pdf
  • Claris Injectables Limited (owned by Baxter) (Gujarat, India), received a warning letter on July 5th 2018 based on the outcome of an inspection ending August 4th 2017. FDA advises the firm that many of the deficiencies were identified in the November 1st 2010 warning letter the firm received. Further, they stress the seriousness of the “history of recurring serious defects in your marketed products.” FDA also recommends the firm retain a qualified consultant(s) to assist them in coming into GMP compliance. The warning letter also includes instructions for data integrity remediation because the ‘…quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture.’ Deficiencies include but are not limited to:
    • OOS results were invalidated without adequate investigation and scientific justification. At the conclusion of this inspection, the firm recalled 5 batches of drug products due to OOS results. In response to the warning letter the firm is asked to provide:
      • A retrospective, independent review of all invalidated OOS (in-process and finished testing) results obtained for products on the U.S. market. Assess whether the scientific justification and evidence was For investigations that conclusively establish laboratory root cause, determine adequacy of the CAPA, and ensure that other laboratory methods vulnerable to the same root cause are identified for remediation. For any OOS results with inconclusive or no root cause identified in the laboratory, include a thorough review of production (e.g., batch manufacturing records, adequacy of the manufacturing steps, raw materials, process capability, deviation history, batch failure history).
      • Provide a summary report of the retrospective review of all OOS investigations for product that remain within expiry. Include a CAPA plan that identifies manufacturing root causes and specifies meaningful improvements. Include the product name, date of the original result, initial and retest OOS results, detailed rationale for invalidating the OOS result, and the outcome of your thorough reassessment. Also, include any additional market actions you intend to initiate because of the retrospective review.
      • A fully remediated OOS investigation procedure, including but not limited to modifications to ensure investigations expand to manufacturing operations when a root cause is not conclusively identified in the laboratory.
      • Updated investigation into the root cause of container-closure system failures leading to increased (b)(4).
      • Testing of retain samples of batches of all drug products within expiry in the U.S. market that used the (b)(4) suppliers (i.e., raw materials, fabricators) associated with excessive (b)(4).
      • A comprehensive, independent assessment of the quality of all (b)(4) container-closure raw materials (parts such as (b)(4), ) and adequacy of all sites who perform (b)(4) fabrication processes. This thorough assessment should also include an evaluation of the adequacy of your qualification program for suppliers of container-closure raw materials ((b)(4) part suppliers) and manufacturers of both (b)(4) and (b)(4).
      • A full description of your (b)(4) material sourcing process and (b)(4) manufacturing process for both (b)(4) and (b)(4). Include the roles and responsibilities of all parties involved in the (b)(4) supply chain and production. Specifically, for all lot of (b)(4) produced since July 1, 2015, provide a detailed summary of all suppliers and manufacturers that you used for your (b)(4) materials, and vendor lot numbers. In each case describe who performed the (b)(4) formation, fabrication, and final assembly (including the specific nature of any in-house operations, such as use of (b)(4) operations). Include any subcontractors or other parties involved with material supply or fabrication.
      • Vendor-generated Certificates of Analysis (COA) for (b)(4) part manufacturers and suppliers, as well as (b)(4) fabricators and assemblers.
      • An assessment of your overall system for investigations into deviations, discrepancies, complaints, OOS results, and failures. Your CAPA plan should include, but not be limited to, improved rigor in reviewing the sources of variation in your operation that may cause deviations, failures, or defects, as well as an extensive remediation of your capabilities to ensure CAPA effectiveness.
    • The FDA investigator observed an operator entering data into the Visual Inspection Test document the day after the operation was completed. The firm is asked to provide:
      • A comprehensive, independent risk assessment of production records including but not limited to your visual inspection documentation to determine the completeness, consistency, and accuracy of reported data. Indicate how you determined that the data you used to release product was attributable, legible, contemporaneously recorded, original or a true copy, and accurate. Include a re-examination of retain samples.
      • Provide a complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed CAPA plan that comprehensively remediates documentation practices, and ensures you retain complete, contemporaneously prepared, and accurate records.
    • Buildings are not maintained in a good state of repair. Investigators identified extensive water damage. They are to provide the following:
      • A comprehensive, independent review of your preventive maintenance program(s) for both facilities and equipment, and a CAPA plan to ensure its effectiveness. Your plan should include but not be limited to contingencies for expected seasonal fluctuations in rainfall.
      • A CAPA plan that formalizes routine, vigilant production management oversight of facility conditions to assure prompt detection of issues, execution of repairs, and other appropriate actions.
      • Your plan to monitor and control humidity levels in the facility to prevent major environmental control issues due to fungi and other microbial contaminants, which were associated with past product recalls by your firm. Also, explain how your will ensure prompt detection of fungi in the facility.
      • Your plan to requalify the facility after remediating the water damage, including your environmental qualification strategy.

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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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