Week of June 30th, 2019 | FDA Sent These Warning Letters to Pharma/Device Companies

A surprisingly busy week for enforcement considering the federal holiday.  Warning letter enforcement includes five drug warning letters published this week, two of which were sent to API re-packagers, and one to a compounding pharmacy.  API re-packagers have been a focus recently for actions most notably for failure to identify the original manufacturer on the CoA that they provide to their customers.

In addition to the two warning letters to API re-packagers, one similar warning letter was posted the week of June 11.  FDA noted in their recent 2018 report On The State of Pharmaceutical Quality that this group is among those not routinely subject to surveillance inspections.  FDA also reported that over the past five years, 27% of recalls are attributed to two repackaging sites: one for APIs, and one for a secondary re-packager.  The press release addressing the three warning letters to re-packagers identified five other warning letters issued to firms in this category for similar violations, and foreign firms in the category who are now subject to import alerts.

On July 2, 2019, Strides (Mumbai, India) disclosed that they received a warning letter based on the outcome of an inspection at their Puducherry site that was classified as OAI.  Ten ANDAs awaiting FDA approval will need to wait until the site is reclassified.  The firm disclosed the OAI status on May 6, 2019. We will address this warning letter when FDA publishes it.


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DRUGS | Aurobindo Pharma Limited

Aurobindo Pharma Limited (India) received a warning letter based on the outcome of an inspection ending February 9, 2019.  While not specifically mentioned, this warning letter is associated with their manufacture of ‘sartan’ medicines, and the subject of high visibility recalls for Aurobindo and other firms.

This is unusually quick for a warning letter.  Aurobindo blamed the impurities on recovered solvents and poor procedures for equipment cleaning, whereas it seems that manufacturing changes and inadequate evaluation of their impact may have been major contributors.

FDA also notes that the firm did not submit supplemental information to report specification changes to a DMF (21 CFR 314.97(a)).  The firm was subject to similar observations at two other sites that manufacture API’s and intermediates.  FDA states that “These failures at multiple sites demonstrate that management oversight and control over the manufacture of drugs are inadequate.”

Further, FDA requests a regulatory meeting with the firm to discuss the problems at Aurobindo Units XI, I and IX.  Note that part of the first bulleted deficiency identifies information from the EDQM that tested their API and found contaminants at an unacceptable level.  At issue seems to be the use of recovered solvent used at their contract manufacturer.

Deficiencies include but are not limited to:

  • Inadequate investigations into impurities that did not include evaluation of key starting materials and other raw materials, including solvent, to cause the impurities. FDA notes that after EDQM identified the contaminants, the company tested a redacted number of batches and confirmed the contamination.  The company then recalled the products.  Although the firm identified recovered solvents and poor cleaning processes as sources of the contaminants, the FDA was not satisfied with their response.
  • Changes to methods and controls were not reported to FDA through an appropriate supplement.  The firm identified impurity levels that exceeded USP limits for “Any other individual impurity” and also exceeded ICHQ3A(R2) reporting threshold for drug substance impurities and the firm’s internal threshold limit for reporting.  FDA reminds the firm that when appropriate, they must submit changes to their DMF and notify all parties who are authorized to reference the DMF.

DRUGS | SnugZ USA, Inc

SnugZ USA, Inc (West Jordan, UT) received a warning letter on June 12, 2019, based on the outcome of an inspection ending November 30, 2018.  The firm manufactures over-the-counter (OTC) products, and FDA identifies five deficiencies.  FDA recommends the firm hire a consultant to assist them in coming into GMP compliance.

The firm’s responses to the form 483 were limited and provided insufficient detail and evidence to support that the corrective actions will bring the firm into compliance.  Further, and likely most damaging, is FDA’s conclusion that “Significant finding in this letter indicate that your QU is not able to fully exercise its authority and responsibilities.”

Deficiencies include but are not limited to:

  • Products were released without testing for identity and strength of the active ingredient and without adequate testing for critical microbial attributes.
  • The firm failed to test incoming raw materials, APIs, and components but instead relied on the supplier’s CoA without verifying the reliability of the data.  No identity tests were conducted either.
  • The firm lacked an adequate Quality Unit and did not have written procedures describing the responsibility and authority of the Unit.  Further, they lack systems and documentation for a variety of fundamental GMP processes.
  • The firm has not validated the manufacturing process, nor do they have an ongoing process monitoring program.  Reference is made to the FDA guidance on Process Validation.
  • The firm failed to conduct cleaning validation, and the investigator observed equipment was “filthy and contained drug product residues.”

DRUGS | Izeen Pharma Inc

Izeen Pharma Inc (Frederick, MD) received a warning letter on May 16, 2019, based on the outcome of an inspection ending July 3, 2018.  The subject of the observations is solid oral dosage forms of levothyroxine and liothyronine for which the firm is a contract manufacturer.

In addition to being adulterated, the products are also misbranded and represent an unapproved new drug for which the firm does not have an FDA-approved application in effect.  FDA suggests the firm hire qualified consultants to assist them in coming into GMP compliance.  The customer recalled all batches of ‘thyroid’ tablets because of the inconsistent or decreasing levels of the active ingredient.

Deficiencies include but are not limited to:

  • The firm’s management of OOS results was inadequate, particularly about identification of root cause.
  • The firm does not have a process for ongoing monitoring of manufacturing processes to ensure they remain in a state of control.
    • “In response to this letter, evaluate drug manufacturing operations to determine the improvements needed to assure you can consistently deliver drug products that meets quality attributes.  Provide a data-driven and scientifically sound analysis that identifies all sources of variability including, but not limited to, raw materials and manual steps (e.g., hand scooping).  Determine the capability of each manufacturing process step and provide your CAPA plan to reduce process variation.”
  • The firm did not test thyroid tablet batches for content uniformity.  The firm continues to assess uniformity of dosage units by weight variation rather than content uniformity.
  • The firm’s stability program is deficient.  The firm failed to follow their stability protocol and also did not include process valuation lots in the stability program.
  • The firm failed to implement adequate controls over laboratory computer systems. The instruments did not have adequate controls to prevent deletion or alteration of raw data files.  Analysts were observed to share usernames and passwords.  Further, users had administrator rights and could delete or modify HPLC files.
    • “Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture” and FDA suggests they contract with a consultant(s) to assist in remediation.

DRUGS | B&B Pharmaceuticals, Inc

B&B Pharmaceuticals, Inc (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.  In addition, the firm distributes drugs that are not found in the FDA listing database, and thus, the drugs are misbranded.

Deficiencies include but are not limited to:

  • The Quality Unit is not adequate and fails to investigate customer complaints regarding subpotent API and did not identify the root cause.   Batch records were not adequately reviewed for completeness and accuracy.  Further, the Quality Unit was not independent of the production operations.
  • The firm has not validated cleaning for equipment used to manufacture high potency compounds including testosterone, progesterone, estrogen, and opioids.
  • The firm generated CoAs that did not identify the name and address of the original API manufacturer and cut and pasted analytical results onto their own letterhead.
  • FDA also states that the firm’s Quality System is inadequate, and recommends that they hire qualified consultants to assist them in coming into compliance.

DRUGS | Asclemed USA Inc. dba Enovachem

Asclemed USA Inc. dba Enovachem (Torrance, CA) received a warning letter on June 11, 2019, based on the outcome of an inspection ending September 27, 2018.  This is another firm that repackages APIs.

Deficiencies include but are not limited to:

  • The firm did not obtain and retain documentation from the supplier supplying the APIs that they repackage.
    • “In response to this letter, provide a retrospective review of drugs currently in distribution that are missing the required original manufacturer information from your suppliers.”
  • The firm provided CoAs to its customers that did not identify the original manufacturer of the API.
  • The firm failed to ensure that calibrations are performed and recorded.  One of the scales used to weigh small amounts (redacted) was last calibrated in 2008.
  • The firm does not conduct annual quality reviews of the APIs that they repackage.

COMPOUNDING PHARMACY | Ideal Specialty Apothercary Inc.

Ideal Specialty Apothercary Inc. (Union, NJ) received a warning letter based on the outcome of an inspection ending August 31, 2017 (no, that’s not a typo).  The FDA identified five violations that rendered the products adulterated and two additional items related to manufacturing under ‘insanitary’ conditions.  This firm was also cited for compounding Avastin for which the FDCA “…does not provide a legal pathway for marketing biological products, including Avastin, that have been mixed, diluted, or repackaged outside the scope of an approved BLA.”  The firm also assigned a beyond-use date of 30 days which exceeds the beyond-use date described in the FDA final guidance from January 2018, ‘Mixing, Diluting or Repackaging Biological Products Outside the Scope of an Approved Biologics License Application.’


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