FDA Warning Letters Week of 5/17/20: Water Systems, Quality Unit Failures, & Inadequate Responses

FDA continues to issue warning letters to firms that distribute unapproved new drugs to prevent or treat COVID-19 infections. In addition, this week FDA posted three warning letters to drug firms, one to a device firm, and one to a compounding pharmacy. We cover these five below.

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Drug Warning and Untitled Letters

Kumar Organic Products Limited

Kumar Organic Products Limited (Gujarat, India) received a warning letter on April 23, 2020 based on the outcome of an inspection ending November 14, 2019.  The firm produces an API that is by definition an in-process material for a finished drug product and therefore subject to 21 CFR 211.  The firm manufactures an OTC topical product(s). FDA recommends the firm hire a qualified GMP consultant to help them come into GMP compliance.

Deficiencies include but are not limited to:

  • The firm’s water system is not appropriately designed, maintained or monitored to ensure it produces water of appropriate quality for its intended use.  (It’s interesting how “water” is redacted but it’s pretty straightforward to figure it out.  Makes no sense to me, particularly when product names are often not redacted.)  Several deficiencies were identified that could lead to formation of biofilms in the system.  Sampling intervals were inadequate and testing of final product cannot substitute for microbiological testing of the water. That’s an approach I’ve not seen before! The firm actually stated they “have not designed [the] system to control bioburden.”

  • The firm failed to test incoming components for identity, nor had they validated and established the reliability of the suppliers’ data.  The firm also uses technical grade of what I assume is glycerine because FDA finds fault with their failure to test for diethylene glycol prior to release for use in the manufacture of product.  While the firm did commit to perform impurity testing for diethylene glycol and related substances and to revise the vendor qualification to include qualification of raw materials to verify the data on the COA, FDA did not accept their response.  FDA deemed the response inadequate because they did not commit to testing all retain samples to ensure they were of adequate quality. 

International Trading Pharm Lab Inc

International Trading Pharm Lab Inc (Paterson, NJ) received a warning letter on April 24, 2020 based on the outcome of an inspection ending October 29, 2019.  The company is a contract testing laboratory.  FDA notes that because they don’t conform to GMPs the APIs that they test are deemed adulterated.  FDA reminds them they are considered an extension of the manufacturers/sponsors operations. They also recommend that the firm hire a qualified consultant to help them come into GMP compliance.  FDA also notes Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you test,” and follows up with a detailed set of requirements for data integrity remediation.  

Deficiencies include but are not limited to:

  • The Quality Unit does not adequately oversee laboratory operations. Several chromatography results, including injections, were not captured in laboratory notebooks, not documented in the OOS investigations which they were intended to support, and not provided for QA consideration during lot release. The firm’s response to the observation was inadequate because the firm did not commit to a review of all chromatography data to determine the extent of this practice. 

  • The firm’s OOS investigations were closed without adequate scientific justification.  During the inspection, the firm told the investigator “…without the permission and authorization of the client, your firm is limited to what can be tested on the sample in case of failure.”  The firm’s response to the observation was not adequate and, further, FDA pointed out this was not correct and that the contract testing laboratory must follow GMPs regardless of the outcome of discussions with clients. 

  • The firm conducted assays and identity testing on multiple API samples without first performing a verification that the method performs adequately under actual conditions of use The firm tried to explain that system suitability served that function, but FDA did not accept that response. 

  • The firm does not have adequate controls to ensure the integrity of electronic test data from HPLCs and GS.  Standalone instruments gave analysts the ability to delete raw data and alter date and time stamps, audit trails were not enabled so it is impossible to determine if any data were manipulated. The firm’s response was inadequate because they did not address the lack of audit trails.  And for anyone who still thinks that paper is the original data FDA notes “You also included a corrective action to print all chromatograms for each analysis. Electronic records are dynamic, and a printout or a static record does not preserve the dynamic record format that is part of the complete original record.

In addition, FDA provides their usual boilerplate language for data integrity remediation.

Blaine Labs Inc

Blaine Labs Inc (Santa Fe Springs, CA) received a warning letter on May 5, 2020 based on the outcome of an inspection ending May 5, 2020.  The firm manufactures a psoriasis treatment that is an unapproved new drug.  FDA identifies unapproved new drug charges within the warning letter and recommends the firm hire a qualified consultant(s) to assist them in coming into GMP compliance.

The deficiencies include but are not limited to:

  • Failure to adequately investigate OOS results, lack of adequate investigation of OOS results for viscosity was cited in the November 2015 inspection.  Quality released material without adequately investigated OOS results, including that for a raw material that failed a microbial specification.  FDA deemed the firm’s response to be inadequate because they did not ensure that failures were adequately remediated.  They also did not commit to a retrospective review of all drug products to ensure that root causes for deviations are adequately established and CAPAs implemented to prevent them from recurring.

  • The firm did not validate the manufacturing process for products nor did they qualify equipment, extensive hold times (that apparently ran into months) or cleaning validation These are repeat deficiencies from a November 2015 inspection.  The firm’s response was inadequate because they did not provide adequate detail on how they would validate processes and cleaning.  Further, FDA refers them to the FDA Guidance on Process Validation.  

  • Water from an unvalidated system that was not adequately monitored was used in cleaning and in manufacture of drug products.  FDA determined that the firm’s response was inadequate because they did not demonstrate they implemented a proper system design that will ensure a state of control. 

  • The Quality Unit failed to exercise its authority and responsibilities as demonstrated by:

    • The firm had multiple versions of a bulk test report that were not approved by Quality.

    • The QC laboratory used loose paper to document original test data which were subsequently transcribed into formal test reports.  The loose paper was not retained or reviewed, laboratory notebooks or worksheets were not used.  In addition, laboratory staff signed off on their own test results without second person verification.

    • No written approved procedures were available that described process validation, equipment qualification, OOS investigations, stability program, or change controls for the manufacturing processes. 


Device Warning and Untitled Letters

Lymol Medical Corporation

Lymol Medical Corporation (Woburn, MA) received a warning letter on April 7, 2020 based on the outcome of an inspection ending February 12, 2020.  The speed with which FDA took enforcement action highlights the potential danger of the firm’s products to the public.  They manufacture reusable bronchoscope systems and silicone stents and seem to have failed to understand the most basic of QSR requirements. 

Deficiencies include but are not limited to:

  • The firm has not validated the cleaning instructions, sterilization instructions, or storage conditions provided to hospitals for the bronchoscope, a reusable device.  

  • The firm has not established adequate documentation for the identification, documentation, and validation and approval of design changes before their implementation.  

  • The firm does not have and maintain documentation and acceptance activities of component parts.

  • The firm has failed to evaluate complaints for potential reporting under MDR requirements.  Further, the complaint process is not adequate because investigations are not performed.  FDA provides detailed examples. 

  • Failure to establish and maintain purchasing documents that describe requirements that must be met for purchased components.  

  • Failure to establish and maintain Device History reports for each batch. 


Letters to Compounding Pharmacies and Outsourcing Facilities

IntegraDose Compounding Services LLC

IntegraDose Compounding Services LLC (Minneapolis, MN) received a warning letter on May 6, 2020.  FDA states that the firm failed to manufacture sterile drugs under appropriate conditions and cite both the FD&C Act and 21CFR211 in the identified deficiencies.  Further, they indicate that the drugs are misbranded because labeling did not provide adequate instructions for use.  And finally, the facility failed to report adverse events as required by law.


BIMO, GCP and GLP Warning and Untitled Letters

No letters were issued this week. 

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