This week FDA posted three GMP warning letters to drug facilities. We also cover a warning letter to an unapproved, misbranded new drug because of the product category.

UNAPPROVED NEW DRUGS | Curaleaf, Inc

Curaleaf, Inc (Wakefield, MA) received a warning letter based on evaluation of information on the firm’s website. We generally do not cover warning letters of this type but chose to do so here because this letter is an example of how FDA enforcement often proceeds in a new area.

FDA has previously issued several warning letters to firms that market cannabidiol products. With recent acquisitions, Curaleaf becomes the ‘…world’s largest cannabis company by both revenue and operating presence.’ FDA often chooses a high profile firm for early actions in a new area they are attempting to regulate.

Basically, the FDA deems that Cureleaf Inc. products are unapproved new drugs and are also misbranded. FDA notes that the firm appears to market the CBD products as dietary supplements, but FDA does not agree with that position because they do not meet the definition of a dietary supplement. FDA also objects to the attempt to market the materials for veterinary purposes.

HUMAN CELLS, TISSUES, & CELLULAR PRODUCTS | Stratus Biosystems

Stratus Biosystems (Grapevine, Texas) received a warning letter on July 1, 2019, based on the outcome of an inspection ending February 28, 2019. The letter identifies six deficiencies, including but not limited to:

  • The process for manufacture of the Amniotic Membrane Patch Allograft is not validated.
  • Materials manufactured from donors that did not meet acceptance criteria were distributed. At issue is contamination by specific micro-organisms.
  • The firm has failed to document whether donors or tissues or cells are acceptable based on the results of donor screening.
  • Failure to retain records following donor eligibility determinations.
  • Failure to adequately clean, sanitize and maintain equipment.  
  • Failure to establish and maintain procedures applicable to current Good Tissue Practices for operations the firm performs.

DRUGS | High Chemical Company

High Chemical Company (Levittown, PA) received a warning letter on July 2, 2019, based on the outcome of an inspection ending February 8, 2019. This inspection began on December 17, 2018.

The firm informed FDA they would “…close the company on or before May 31, 2019”. The firm manufactures Sarapin, a non-sterile botanical-derived API intended for use in sterile injectable finished drug products. 

Deficiencies include but are not limited to:

  • The firm does not test the API for strength, dry weight, residual pesticide, and heavy metals. Further, the firm informed FDA that the active ingredient in this botanical drug could not be identified.
  • The firm could not provide any data to support the two-year expiry date for the API. Their response to the form 483 did not address this observation.
  • The API is also misbranded because the labeling does not state  “Caution: For manufacturing, processing, or repackaging.” The API is sold to compounding pharmacies for further processing.

DRUGS | Indoco Remedies Limited

Indoco Remedies Limited (Mumbai, India) received a warning letter on July 9, 2019, based on the outcome of an inspection ending January 25, 2019.

Among the other deficiencies identified, the FDA states that the firm’s quality system is inadequate, they should hire qualified consultants to assist them in coming into compliance with CGMPs, and they fail to have an adequate ongoing process monitoring program to ensure the manufacturing process remains under control.

As if that and the other deficiencies aren’t enough, Indoco must provide documentation addressing the usual FDA boilerplate requirements for data integrity remediation.

Strangely enough, the firm is not placed on import alert. Providing all the information that FDA requests will be a lengthy process, remediation here will not happen quickly.

The three GMP deficiencies include but are not limited to:

  • Batch records do not contain complete information. The compression values in the paper batch records are not in agreement with those in the programmable logic controller (PLC). The handwritten values are within the acceptable ranges; the values in the PLC were outside the established process parameters. The same situation existed for the filling depth and automatic weight control value. FDA notes that this is a repeat observation from an inspection in March 2018. In their response to the inspection, the firm “…did not commit to perform a comprehensive retrospective evaluation of the integrity of data throughout the manufacturing process.”
  • The firm’s investigation into the discrepancies in the batch records was inadequate because it did not include the following:
    • “A review of the integrity of the data by contrasting handwritten and electronic data for all process control values recorded by your PLC during (b)(4) tablets manufacture to determine if other discrepancies had occurred.”
    • “A sufficient extension of your investigation to other strengths of (b)(4) batches and other products manufactured at your facility.”
    • “A substantive root cause for the significant variability of compression machine process control values throughout the manufacturing of (b)(4) tablets.”
    • “A CAPA plan to resolve the root causes of this variability.”
  • Laboratory records did not include complete data, and the firm failed to retain raw laboratory data. OOS management was inadequate because some OOS events were not recorded and investigated.
  • Further, the firm must provide responses to the FDA’s long version of boilerplate narrative on data integrity remediation.