FDA Warning Letters Week of 11/10/2019: FD&C Act and Continued Sartan Enforcement

A busy week on the warning letter enforcement front.  We provide one warning letter to a compounding pharmacy, one to an API manufacturer, and three to drug product manufacturers.  For those who use recovered solvents in their manufacturing process, they would be well served to read FDA’s recommendations to Mylan on the topic of material management.

In addition, Greenbriar International, dba Dollar Tree, received a warning letter for “receipt in interstate commerce of adulterated drugs and the delivery or proffered delivery thereof…”.  This warning letter sends a message that should be considered by all who distribute their own label OTC and cosmetics products and the need to adequately secure their supply chain and ensure supply chain members are compliant with appropriate CGMPs.

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DRUGS | MSM Nutraceuticals, LLC dba MSM Health Solutions

MSM Nutraceuticals, LLC dba MSM Health Solutions (Phoenix, AZ) received a warning letter on October 24, 2019 based on the outcome of an inspection ending May 8, 2019.  The firm manufactures OTC drug products.  They also were cited for the manufacture of unapproved new drugs.

In several of the instances where FDA asks for additional information in response to the warning letter, they request an “independent assessment“.  This strongly suggests that they don’t feel that the firm is capable to perform these evaluations alone.  The firm initiated a recall of all sterile ophthalmic eye drops.

Further, the firm has stopped drug production at this site and is considering the use of contract manufacturers.  FDA reminds them they are responsible for drug quality regardless of the agreement with the contract facility.  Finally, the FDA suggests they hire a GMP consultant to help them come into GMP compliance.

Deficiencies include but are not limited to:

  • Drug product was released for distribution without testing for the identity and strength of the active ingredient, the absence of objectionable microorganisms and appropriate microbiological limits.
  • The manufacturing process has not been validated, nor is there an ongoing process monitoring program.  Further, the water system is not adequate to consistently produce USP purified water.
  • The firm does not have stability data to support expiry dating.
  • The firm did not test incoming materials for identity but relied on the vendor CoA.  Vendors were not qualified.  The firm uses glycerin in the manufacture of at least one product, and it is not clear whether they have tested for DEG and EG.

DRUGS | Swabplus, L.P.

Swabplus, L.P. (Rancho Cucamonga, CA) received a warning letter on October 31, 2019, based on the outcome of an inspection ending April 11, 2019.  The firm manufactures OTC drug products and is a contract manufacturer.

Deficiencies include but are not limited to:

  • The firm failed to test incoming components for identity and other quality attributes.  The firm relied on vendors’ CoA from unqualified vendors.  Also, the firm failed to adequately monitor the water system.
  • Analytical methods are inadequate or are not validated.  Microbial test methods aren’t supported by growth promotion of media, and the anti-microbial preservatives are not neutralized so that the firm is confident of their results.
  • The quality unit was inadequate and did not have adequate written responsibilities and procedures.
  • The firm did not exercise adequate controls over computer systems.  For example, there was not a unique user ID established nor was data properly backed up.

DRUGS | Cadila Healthcare Limited

Cadila Healthcare Limited (Ahmedabad, India) received a warning letter on October 29, 2019, based on the outcome of an inspection ending May 3, 2019.  No import alert was imposed, and on October 2, 2019, the firm informed FDA they would permanently cease production of sterile injectable drugs for the US market that were made at this site.  FDA noted that if the firm would ever intend to resume production, they would need to remediate the deficiencies.  FDA wants the firm to provide its plan for moving the products to other sites if they plan to do so.

FDA issued two previous warning letters to Cadila in 2015 (see here and here).  FDA states that Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.”  Here is the 23-page form 483 associated with the inspection that preceded the warning letter.

Deficiencies identified in the warning letter include but are not limited to:

  • Inadequate cleaning and equipment flaws led to cross-contamination of materials that were made in shared equipment.  The warning letter documents evidence of cross-contamination using swabs taken from shared equipment and testing of reserve materials.  As a result of this testing, the firm initiated numerous recalls.
  • Investigations into failures in periodic requalification of sterilizing cycles are inadequate.
  • The firm has a variety of failures in aseptic processing, smoke studies, and inadequate cleanroom design.
  • The environmental monitoring program is inadequate in the setting of limits before investigations are necessary, and the definition of ‘intervention’.

DRUGS | Mylan Laboratories Limited – Unit 8

Mylan Laboratories Limited – Unit 8 (Andhra Pradesh, India) received a warning letter on November 5, 2019, based on the outcome of an inspection ending June 5, 2019 that resulted in an 11-page form 483.  The firm manufactures APIs and is yet another firm that has been identified to have issues with potential carcinogenic impurities probably originating from recovered solvents.

The warning letter specifically mentions the valsartan API as a product implicated with this contamination.  The FDA recommends the firm hire a qualified GMP consultant to assist them in coming into GMP compliance.  The warning letter does not mention imposition of an import alert.

Note that FDA asked for “third party review” of some of the processes and procedures, suggesting they have little confidence in a review that may be performed by Mylan itself.  A review of material system is among the processes the third party should review.  The focus on solvents in this and other recent warning letters, and their recovery/storage/use, should encourage all firms that use organic solvents to evaluate their practices and procedures to ensure these materials are not sources of contamination or product cross-contamination.

The larger story, including firms other than Mylan, addresses the complexity in the drug supply chain.  A problem at one supplier of API or recovered solvents can impact many other firms and many products as we’ve seen with the ‘sartan’ contamination.  (Note: read here to learn more about the enforcement actions against ‘sartan’ manufacturers.)  The deficiencies described in this area are not ‘rocket science’ or new interpretations of requirements.  Rather, this is simply failure to follow fundamental GMPs.  The two deficiencies are well worth reading for their depth of detail.  The warning letter notes that by December of 2018 the firm recalled all lots of valsartan API.

The firm is also no stranger to warning letters.  Warning letters were issued in 2018 and 2015.

In comparing the form 483 to the warning letter, it is interesting to note that observations 5 and 6, both with multiple examples, in the form 483, are not included in the warning letter.  These observations identify inadequacy in analytical test methods and failure to qualify laboratory analytical instruments.

Deficiencies in the current warning letter include but are not limited to:

  • The firm does not have adequate procedures for receipt and testing of raw materials based on the presence of NDMA or NDEA impurities in the resulting API manufacturing process and materials.  Ultimately the firm determined that the impurities resulted from recovered solvents used in the manufacturing process.  Further, while recovered solvents were purchased from several contract manufacturers, there is no record of which tanks were used to store these solvents.  In addition, contaminants were found when solvents were recovered in-house, too.
  • Non-dedicated equipment was not cleaned in a way that provided assurance that it was adequate to prevent contamination and carry over among products.  Visible residues were identified on equipment labeled as clean, and testing determined that the stain was residual valsartan API.  FDA notes that “Cross-contamination cannot be assumed to be uniformly distributed and testing alone is insufficient to mitigate the observed contamination hazards.”

COMPOUNDING PHARMACY | Farmville Discount Drug Inc. DBA Best Value Drug

Farmville Discount Drug Inc. DBA Best Value Drug (Farmville, NC) received a warning letter on July 9, 2019 (yes, it was just posted) based on the outcome of an inspection ending November 17, 2017 (no, that’s not a typo).

This begs the question of what good does it do to issue a warning letter when the public has been exposed to products made with poor aseptic practices for another two years after the inspection? 


DRUGS | Greenbrier International, Inc dba Dollar Tree

Greenbrier International, Inc dba Dollar Tree (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.  In addition, some of the imported products also are regulated as cosmetics.

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.”  Further, FDA states The inspection revealed that you had limited manufacturing operations at your corporate headquarters.  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).”  This is the section of the Act that identifies “Prohibited Acts”.

FDA also reminds the firm they are responsible to ensure that all drugs they distribute are manufactured under CGMP.   FDA asks that 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 own supply chain to determine if similar deficiencies exist.  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.

Deficiencies include but are not limited to:

  • Drugs were purchased from multiple firms outside the US who had received warning letters between 2016 and 2019.  Drugs made by these firms are deemed to be adulterated and the firms were placed on the FDA import alert list.  When these warning letters were issued, FDA notified Dollar Tree. 
  • Greenbriar stated they ceased importing drugs from establishments placed on import alert, but FDA says that the “…data demonstrate this is not always the case.  In response to this warning letter the firm asked to provide:
    • “A detailed plan to ensure you do not receive or deliver adulterated drugs in interstate commerce, in violation of section 301 © of the FD&C Act, 21 U.S.C. 331©.”
    • “Items in your plan should include a full evaluation of your supplier and contract manufacturer evaluation program, including a plan to audit your suppliers. Furthermore, you should also include a full reconciliation of any drugs from the manufacturers listed above, as well as for all firms or drugs currently on FDA import alerts, to determine if you have any remaining drugs in your possession, either in your distribution network or in retail stores under the Dollar Tree, Family Dollar, or any other retail store brands in your network.”
  • Greenbriar directed their contract manufacturers and suppliers to use Bureau Veritas to test articles that Greenbriar distributed.  The CMOs stated they relied on laboratory reports “bearing both Greenbrier International and BVS logos” to release products to the US market.  During an FDA inspection of a BVS laboratory, a BVS staff member states “…its test results were not suitable to make release decisions of drug products for distribution into the U.S. supply chain.”  Bureau Veritas is a global testing/certification organization serving a variety of industries.

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