We’re back this week after a week with no issued warning letters (week of September 22nd). We include the warning letter issued to Lupin Limited which seems to show they haven’t corrected their shortcomings since the November 2017 warning letter.

Also, in another first-of-a-kind set of warning letters, the FDA and DEA issued joint warning letters to four online networks which are marketing unapproved opioid medicines. As unapproved new drugs, they are also misbranded because they do not include adequate instructions for use. A total of 10 websites were included in this illegal effort. The four firms include: Divyata, Euphoria Healthcare Pvt. Ltd., JCM Dropship, and Meds4U. FDA issued a press release regarding these warning letters.

DRUGS | Lupin Limited

Lupin Limited (India) received a warning letter on September 10, 2019 based on the outcome of an inspection ending December 4, 2018. The site manufactures both APIs and drug product.

The warning letter identifies only three deficiencies but also notes that repeat problems have been identified at at least two other sites (see the Warning Letter to the Goa and Indore, India sites from November 2017) and states, “These repeated failures at multiple sites demonstrate that management oversight and control over the manufacture of drugs are inadequate. You should immediately and comprehensively assess your company’s global manufacturing operations to ensure that systems, processes, and the products you manufacture conform to FDA requirements.” The warning letter does not mention any import alerts.

Deficiencies include but are not limited to:

  • OOS investigations are inadequate because they did not determine the cause of the OOS nor did they implement corrective and preventive actions. This seems to be a frequent occurrence because FDA specifically mentions “a substantial number of OOS assay investigations for multiple drug products.”
  • Process validation is not adequate because the firm did not adequately identify sources of variation and demonstrate an ongoing state of control with process monitoring. This is particularly important because the active ingredient is a small proportion of the formulation. Further, the firm failed to reassess factors that may impact process consistency and batch uniformity throughout the product lifecycle. Batch failures, including those for assay, do not have identified root cause.
  • The investigator saw unknown residues on multiple non-dedicated product contact surfaces though the equipment was labeled as “clean.” The FDA concluded their cleaning process for manufacturing equipment was inadequate.

DRUGS | Dermameal Co., Ltd.

Dermameal Co., Ltd. (South Korea) received a warning letter on September 12, 2019 based on the outcome of an inspection ending March 29, 2019. The firm is a contract manufacturer of OTC products.

The firm was placed on import alert 66-40 on July 19, 2019. The FDA encourages them to hire a qualified consultant(s) to assist them in coming into GMP compliance. The deficiencies identified in the warning letter are those that have been way too common for OTC manufacturers.

  • Twenty-six of 41 lots reviewed did not have microbiological testing completed prior to product distribution. The firm said their customer agreed with the practice; FDA did not.
  • The stability program did not include assay testing on stability samples. In addition, the firm does not have an ongoing stability program.
  • Incoming raw materials, including APIs are not tested for identity. Rather, the firm accepts materials on the basis of the CoA from unqualified suppliers. As with other OTC manufacturers, they missed the fundamentals. FDA reminds them that they can rely on a CoA only when the supplier is qualified and they repeat testing at defined intervals. And they must always test for identity upon receipt. Further, they appear to receive glycerin and while the letter is redacted it appears they do not test for either DEG or ethylene glycol according to FDA guidance.
  • The firm has not validated the manufacturing processes and does not have a program for routine process monitoring. The firm committed to perform validation upon the client’s next order of product(s).
  • Cleaning has not been validated for non-dedicated manufacturing equipment. And when they did perform cleaning, it was not documented.

DRUGS | Shanghai Institute of Pharmaceutical Industry

Shanghai Institute of Pharmaceutical Industry (China) received a warning letter on August 29, 2019 based on an inspection scheduled to end December 4, 2018. The firm is a contract testing lab that provides identity testing and characterization of APIs for ANDA submissions.

The firm received the warning letter because they refused the FDA planned surveillance and pre-approval inspection. It’s interesting that they were not placed on import alert, particularly because this happened ten months ago. Because a PAI was involved, I imagine the sponsor would have received a CRL because a key facility was not available for inspection.