Firms that thought it wasn’t necessary to monitor import alerts that may have been placed against their suppliers received another lesson from FDA in January that they are wrong.  This is not the first warning letter of this type—five other warning letters address the topic including ones issued in 2019 to:

We’ll look at the others in turn, but let’s start with the warning letter that FDA posted on January 22, 2020.

Cosmelab Co Ltd

Cosmelab Co Ltd in South Korea received a warning letter on January 9, 2020 based on the outcome of an inspection ending July 17, 2019.  The firm manufactures OTC drug products.  The firm is cited for having firms on their suppliers list who have been placed on import alert by FDA.  FDA states that “…your use of this supplier on Import Alert 66-40 led to the appearance of adulteration of your drugs.”  The warning letter includes only one deficiency, failure to establish an adequate quality unit, with multiple examples of failure to comply with GMPs.  The single deficiency and multiple examples include but are not limited to:

  • The firm failed to establish an adequate quality unit.  Examples include but are not limited to failure to conduct and review assay tests prior to distribution of drug product, and release of drug product manufactured by a contract manufacturer that is on import alert 66-40.  Further, the firm being inspected was unaware that their CMO was on import alert.  The firm stated “…that a lack of understanding of FDA drug regulations contributed to your not establishing a dedicated quality unit.  You committed to hire a consultant knowledgeable about FDA regulations.”  Note that FDA requests an “independent assessment” indicating that they don’t feel the firm is capable of conducting a valid and effective assessment on their own.  This has become common text in warning letters over the past year.  FDA also placed Cosmelab Co Ltd on import alert as a result of the deficiencies.  It’s useful to review what FDA expects from the firm in terms of determining the scope of the problem and remediation.  In response to the warning letter, the information that the firm is asked to provide includes but is not limited to the following:
      • “A comprehensive independent assessment and remediation plan to ensure your QU is given the authority and resources to effectively function.  The assessment should also include, but not be limited to:
          • A determination of whether procedures used by your firm are robust and appropriate
          • Provisions for QU oversight throughout drug product distribution to evaluate adherence to appropriate practices
          • A complete and final review of each batch and its related information before the QU disposition decision
      • A detailed plan for ongoing assessments of each lot of component used for production of finished drug product to meet appropriate standards of identity, strength, quality, and purity.  Outline your plans to establish a robust supplier qualification program, including a detailed supplier qualification and audit program that specifies how you ensure that oversight of suppliers is commensurate with risk to finished product.”

FDA clearly takes failures in this area seriously, particularly when FDA provides firms the tools and information to monitor Import Alerts for their suppliers and CMOs.  This monitoring should be a component of any comprehensive GMP Intelligence program.  FDA Import Alerts are published almost daily and are straightforward to monitor.  In general for the drug area, I focus on the following Import Alerts, though there are dozens of others in the drug and device area that may be relevant depending on the nature of the business receiving the materials:

  • 66-40 (Detention without Physical Examination of Drugs from Firms Which Have Not Met Drug GMPs)
  • 66-41 (Detention without Physical Examination of Unapproved News Drugs Promoted in the U.S.)
  • 99-32  (Detention without Physical Examination of Products from Firms Refusing FDA Foreign Establishment Inspections)

Let’s go back to the related warning letters issued in 2019, particularly the two issued to Greenbrier International and Vipor Chemical Private Ltd.

Greenbrier International, Inc dba Dollar Tree

Greenbrier International, Inc dba Dollar Tree located in Chesapeake, Virginia received a warning letter on November 6, 2019 based on the outcome of an inspection ending January 18, 2019.  The inspected site operates as a warehouse for storage of a variety of finished drug products distributed to Dollar Tree stores with a Dollar Tree label.  At issue is the GMP status of a variety of contract manufacturers, located outside the US, who produced these drug products.

FDA states: “inspections revealed violative conditions at multiple foreign drug manufacturers that supplied drugs to your distribution network.  However, the CGMP violations identified at your suppliers caused drug products manufactured by these firms to be adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act).  Your receipt in interstate commerce of adulterated drugs, and the delivery or proffered delivery thereof, is a violation of section 30 I (c) of the FD&C Act, 21 U.S.C. 33 I (c).”

Deficiencies in the warning letter do not cite 21CFR211 but rather cite the FD&C Act, 21 USC 331(c), the section identifying Prohibited Acts.  FDA also reminds the firm they are responsible to ensure that all drugs they distribute are manufactured under CGMP.  FDA asks the firm “to schedule a meeting [with FDA] to discuss the adequacy of the corrective actions you proposed to prevent the continued introduction of adulterated goods into interstate commerce.”   Firms similar to Dollar Tree that distribute OTC products under their own name would be well advised to evaluate their supply chain to determine if similar deficiencies exist.  

Vipor Chemical Private Ltd

Vipor Chemical Private Ltd located in India received a warning letter on January 29, 2019 based on the outcome of an inspection ending February 24, 2018.  The firm makes APIs and had not responded to the Form 483 observations at the time the warning letter was issued.  The firm from which Vipor Chemical purchased API had been placed on Import Alert 99-32 (refusing an FDA inspection) on October 10, 2017.

When Vipor Chemical repackaged these API(s) and provided them to customers, the accompanying certificate of analysis did not identify the name and address of the original API manufacture.  Thus, Vipor Chemical’s customers were not able to determine the true supply chain for their purchase and could not know the original manufacturer was the subject of an import alert.

Among other requests FDA makes of the firm, they ask them to identify any actions they “…have taken or will take, such as notifying customers, recalling drugs, or invalidating previously issued COA for any drugs still within their labeled retest dates; and a recently issued COA that includes the required information, as well as a batch certificate.”  Again, the nature of their requests makes clear the importance the FDA places on supply chain accountability and traceability that may put consumers at risk.

And finally, the three warning letters addressed below do not cite use of materials from a supplier that is in import alert.  They do, however, stress the criticality of providing complete information from the original API manufacture on any Certificate of Analysis prepared by the repackager.  This information is essential for customers to understand and monitor their complete supply chain.

Spectrum Laboratories

Spectrum Laboratories received two warning letters this year, one on June 4, 2019 and one on July 31, 2019.  These are two very similar warning letters issued to the firm’s CEO based on inspections of sites in California and New Jersey respectively.  While not addressing suppliers that are on import alert, they demonstrate the importance of complete information on any repackaged product.

A deficiency in each of the warning letters addresses the COA that the firm prepares for repackaged APIs which are sold to other firms, including compounding pharmacies.  The CoAs prepared by Spectrum Laboratories do not include information identifying the original manufacturer.

The firm responded to the Form 483 observation asserting that their current practice is sufficient, and customers can request additional information.  That approach was not satisfactory for FDA.  Six of the repackaged APIs list Spectrum’s name on the label—this falsely represents that spectrum is the manufacturer.  Thus, FDA deems these APIs to be misbranded because the labels are false and misleading.  FDA also notes that both of the Spectrum sites had similar deficiencies and thus “…failures at multiple sites demonstrate that management oversight and control over the manufacture of drugs are inadequate.”

B&B Pharmaceuticals, Inc

B&B Pharmaceuticals, Inc in Englewood, CO received a warning letter on June 4, 2019, based on the outcome of an inspection ending October 30, 2018.  The firm repackages APIs.  The firm generated CoAs that did not identify the name and address of the original API manufacturer and cut and pasted analytical data from the original supplier onto their own letterhead.

This warning letter, unlike the one to Spectrum Laboratories above, does not declare that the APIs are misbranded due to the inaccurate labeling.  B&B Pharmaceuticals, Inc notes that their parent company is Fagron.  Fagron is active in pharmaceutical compounding in 35 countries and their website identifies them as the “world’s leading pharmaceutical compounding company”.

Conclusion

It is clear that FDA places a high priority on ensuring a secure and accurate supply chain and that firms and customers bear this responsibility based on information available on the FDA website and on documentation accompanying purchased products, particularly Certificates of Analysis.  The FDA provides the appropriate tools and information on their website for firms to monitor whether their suppliers have been placed on import alert and to take appropriate action.  This is equally important for re-packagers of both drugs and APIs to ensure the original manufacturer is identified on any documentation provided to customers so that the customer may also ensure that none of the participants in the supply chain are identified on an active Import Alert. 

In addition to monitoring import alerts, GMP auditors should consider this topic during due diligence efforts and routine audits of both company-owned sites and CMOs.  The cost of being wrong is substantial as indicated by the issuance of these warning letters in 2019.

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