Another busy week on the warning letter enforcement front. Again, like last week, FDA warning letters are led by the Center for Tobacco Products issued to those who sell e-cigarette vaping products. Here we address one warning letter to a device firm, one to a fertility clinic with similar issues to one posted last week, and four to drug firms. This includes the warning letters to Glenmark and Torrent located in India, both of which were announced last week but not yet posted by FDA.

DEVICES | Denterprise International, Inc

Denterprise International, Inc (Ormond Beach, FL) received a warning letter on October 9, 2019 based on the outcome of an inspection ending May 6, 2019. The firm manufactures dental X-ray sensors/products.

Deficiencies include but are not limited to:

  • While not identified on the form 483, the firm failed to establish procedures for design controls. FDA provides 8 specific examples. It is interesting that the first deficiency in the warning letter, including 8 examples, was not noted on the form 483.
  • The firm failed to adequately establish procedures to ensure the evaluation of suppliers on their ability to meet quality requirements. This is identified as a repeat observation from a 2018 inspection and an Untitled Letter from August 8, 2018.
  • Complaint records do not include the required information in the regulations. This is also identified as a repeat observation from the 2018 inspection and the Untitled Letter from August 8, 2018.
  • The firm has not performed internal quality audits. This is a repeat deficiency from FDA inspections conducted from July 25-29 2016, March 7-12 2018, and on the Untitled Letter dated August 8, 2018.
  • The firm has not established and implemented finished device acceptance criteria. Again, this is a repeat deficiency from FDA inspections conducted from July 25-29 2016, March 7-12 2018, and on the Untitled Letter dated August 8, 2018.
  • The firm does not have procedures for device history records. Another repeat deficiency from FDA inspections conducted from July 25-29 2016, March 7-12 2018, and on the Untitled Letter dated August 8, 2018.
  • The firm failed to immediately report accidental radiation occurrence to the FDA as required by 21 CFR 1002.20, and provide several examples that were submitted as customer complaints.

HUMAN CELLS/TISSUES | Westlake IVF LLC

Westlake IVF LLC (Austin, TX) received a warning letter on September 30, 2019 based on the outcome of an inspection ending May 31, 2019.

Five deficiencies all address donor eligibility: failure to complete screening procedures, failure to establish adequate procedures for all steps in testing; failure to test specimens for selected infectious agents.

Similar to the warning letter to a fertility clinic last week, FDA notes: “If you still have oocytes in storage from donors who were not tested for WNV and/or screened for risk factors for relevant communicable diseases or disease agents in accordance with the regulations in 21 CFR Part 1271, please note that FDA considers the donor eligibility determinations to be incomplete for these donors. Therefore, as required by 21 CFR 1271.60(a), you must keep these HCT/Ps in quarantine.”

DRUGS | The Skin Atelier, Inc

The Skin Atelier, Inc (Goshen, NY) received a warning letter on October 1, 2019 based on the outcome of an inspection ending April 4, 2019. The firm manufactures a variety of OTC products.

FDA recommends that the firm hire qualified CGMP consultant to assist them in coming into GMP compliance. FDA noted that the firm declined to provide photocopies of their product formulation procedure, and did not provide the proportion of ingredients. They were reminded that this may be considered to be limiting an inspection. The firm was also cited for distributing unapproved drug products, and as such they are also misbranded.

Deficiencies include but are not limited to:

  • Finished drug product testing did not include identity and strength tests for each active ingredient. Also, the adequacy of the microbiological tests are in question. 
  • The Quality Unit is inadequate because the firm lacked fundamental and important SOPs for GMP processes.
  • The stability program was inadequate because temperature and humidity in chambers were not continuously monitored, there were no real-time stability studies for all drug products, and potential degradation products of the active ingredient were not monitored.
  • The firm did not have cleaning validation for non-dedicated manufacturing equipment.

DRUGS | Coral Pharmaceuticals LTD

Coral Pharmaceuticals LTD (Grand Bahama, Bahama) received a warning letter on October 9, 2019 based on the outcome of an inspection ending May 24, 2019. The firm manufactures homeopathic drug products.

The firm is reminded of their responsibilities as a contract manufacturer, and are recommended to hire a qualified consultant to assist them in coming into compliance with the regulations. The firm was also placed on Import Alert 66-40 on September 25, 2019.

Deficiencies include but are not limited to:

  • The firm manufactures a drug from a toxic material and the process is not validated. The firm’s data do not support that the drug product is at the concentration specified on the product label.
  • The firm did not conduct identity testing of the toxic ingredient prior to releasing the product for use in manufacture. Further, the firm relied on the supplier’s CoA without qualification of the vendor.
  • The firm did not establish Quality Unit responsibilities for drug product approval.

DRUGS | Glenmark Pharmaceuticals Limited

Glenmark Pharmaceuticals Limited (Baddi, India) received a warning letter on October 3, 2019 based on the outcome of an inspection ending April 20, 2019. The warning letter was sent to the Chairman and Managing Director of the firm in Mumbai, India. The firm manufactures drug product. There is no indication of an import alert from the warning letter text.

Deficiencies include but are not limited to:

  • The firm failed to identify root cause of deviations and implement lasting corrective actions. At issue is investigations into customer complaints regarding their topical products. The problems were likely associated with temperature excursions during the shipping of the drug product. Inadequate investigations into temperature excursions was a repeat observation from a previous inspection. Further, the firm failed to identify multiple OOS events, and over 70 customer complaints.

DRUGS | Torrent Pharmaceuticals

Torrent Pharmaceuticals (Gujarat, India) received a warning letter on October 8, 2019 based on the outcome of an inspection ending April 16, 2019. There is no mention of an import alert in the warning letter. FDA recommends the firm employ a qualified consultant to assist them in coming into GMP compliance.

Beyond the specific subjects in this warning letter, the FDA notes “Repeated failures at multiple sites demonstrate that executive management oversight and control over the manufacture of drugs is inadequate…You should immediately and comprehensively assess your company’s global manufacturing operations to ensure that systems, processes, and the products manufactured conform to FDA requirements.”

This is yet another firm that manufactures “sartan” drug products that have been the subject of recalls for the presence of potential carcinogenic compounds. The warning letter addresses data the firm generated in support of an “alternate API” supplier and identifies failures in process validation and OOS management.

Deficiencies include but are not limited to:

  • The first three process validation lots failed for dissolution and assay. A fourth batch also failed specifications for dissolution, and Quality rejected the four PV batches. FDA states “You also failed to provide adequate justification in your process validation protocols to support approval of the alternate API with known PV failures.” The firm developed a new interim protocol to justify use of the alternate API which failed the initial process validation and released lots of Losartan Potassium products to the US market.
  • Investigations into multiple OOS events did not result in an assignable root cause or lacked scientific justification. Included here was the invalidation of multiple OOS events with an invalidation rate of 60-70%. This is identified as a repeat failure from a 2017 inspection at the Indrad facility and at the Gujarat facility in 2019. “Repeated failures at multiple sites demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.”