FDA appears to be catching up a bit after a couple of very slow weeks for warning letters issued for drugs, biologics, devices, and compounding pharmacies. This week FDA posted one warning letter to a device firm, two to compounding pharmacies, one to an HCT/P manufacturer, and two to drug firms.

Normally we don’t publish warning letters issued for unapproved new drug products, but this week four of them were posted for drugs labeled as homeopathic, so we include links to them. 

Drug Warning and Untitled Letters

EUCYT Laboratories LLC

EUCYT Laboratories LLC (Las Vegas, NV) received a warning letter from CBER on June 4, 2020, based on the outcome of an inspection ending November 21, 2019. The firm manufactures products derived from human umbilical cord blood and a single exosome product. All products are for allogeneic use. The products meet the definition of HCT/Ps and are subject to the regulations in 21 CFR 1271. The warning letter listed 13 deficiencies in total.

Deficiencies include but are not limited to:

  • Since operations began in April 2018, the firm has failed to document whether donors sourced from the company’s suppliers are eligible based on donor screening and donor testing. The donors are not screened for the Zika virus. Overall, the firm has not established procedures for determining donor eligibility or for accepting or rejecting donations.

  • Aseptic processes have not been validated since the firm began operations in April 2018.

  • There is no adequate SOP(s) for environmental monitoring or personnel monitoring.

  • The firm has not established validated cleaning processes nor do they maintain cleaning records.

  • The firm had 152 sterility failures between April 2018 through November 2019. No corrective actions have been implemented.

  • Expiry dating is assigned without supporting data.

  • No procedures exist for documenting and managing complaints.

  • Penicillin was used during the manufacture of some products and there is no documented testing that cross-contamination of other products, with penicillin, occurred.

Fenwal International

Fenwal International (Maricao, Puerto Rico) received a warning letter on May 14, 2020, from CBER based on the outcome of an inspection ending September 26, 2019. The firm manufactures blood-pack units and InterSol a platelet additive solution. 

Deficiencies include but are not limited to (redactions for deficiency 2 and 3 were extensive so it was impossible to understand what actually happened):

  • The FDA investigator notes data differences between the actual observed microbial growth and the recorded results. Several instances of undercounting CFU’s were noted

  • FDA stated that “The data integrity breaches identified during our inspection raise serious concerns regarding the validity of all results documented by your quality control laboratory,” and “Your quality unit does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture.” 

Cosmaceutical Research Lab Inc

Cosmaceutical Research Lab Inc (Surrey BC, Canada) received a warning letter on May 29, 2020, based on the outcome of an inspection ending November 22, 2019. In addition to adulterated products, the firm also distributes unapproved new drug(s) which are misbranded. FDA recommends they employ a qualified consultant to assist in bringing them into GMP compliance. Further, FDA states “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 asks them to provide specific information regarding their data integrity plans in response to the warning letter. 

Deficiencies include but are not limited to:

  • The firm performed extra HPLC injections without an identified purpose and with suspect nomenclature. More clearly put, these appeared to be test injections. FDA also found torn quality and production documents in the trash. 

  • The firm lacked impurity testing, including for a potentially carcinogenic impurity. Furthermore, the test methods the firm did employ were not appropriately evaluated for accuracy or precision.

  • The firm lacked both stability-indicating methods and forced degradation studies for drug products.

  • The firm does not adequately manage OOS events and invalidates results without adequate justification. 

Takeda Pharmaceutical Company Limited

Takeda Pharmaceutical Company Limited (Japan) received a warning letter on June 9, 2020, based on the outcome of an inspection ending November 26, 2019. The FDA deemed the company response inadequate because it lacked detail or evidence of corrective actions. 

Deficiencies include but are not limited to;

  • The Quality Unit permitted aseptic filling operations to resume, after a shutdown, without performing a media fill simulation as required by procedure. During the shutdown, activities were performed that would have compromised control over the cleanrooms. In addition to failure to follow their own procedures, the firm did not assess the impact on sterility assurance when a media fill was not conducted as part of the manufacturing restart. 

  • The media fill program is inadequate: Integral vials were removed and not incubated and this practice was not justified; operators exhibited poor aseptic technique; there is a lack of traceability of materials used in the aseptic processing area. 

  • The firm failed to investigate equipment malfunctions which may have resulted in the occurrence of black metal particles embedded in lyophilized cake; the firm failed to ensure that equipment functioned as intended.  Multiple in-house investigations failed to identify a root cause for the forging particulates. The firm recalled Natpara on September 5, 2019, for particulates, likely rubber particulates from the rubber septum. 

Manufacturers of Homeopathic Drugs

FDA posted four warning letters to manufacturers of homeopathic drugs. These drugs are unapproved injectable drugs that are labeled as homeopathic. FDA states they have not approved any drugs labeled as homeopathic, perhaps suggesting they plan to move forward in doing so. 

The warning letters were issued to:

Device Warning and Untitled Letters

Klarity Medical Products LLC

Klarity Medical Products LLC (Newark, OH) received a warning letter dated June 8, 2020, based on the outcome of an inspection ending February 25, 2020. The firm is a specification developer and manufacturer of body support devices used during radiation treatment. The firm considered the product in question to be a design change to another of the firm’s FDA cleared devices. FDA took issue with that conclusion and deemed the product to be a new device. The firm also manufactures “Klarity Vacuum Bags for Radiation Therapy” which the FDA determined was misbranded because the firm “failed or refused to furnish material or information.” regarding the device. Several are repeats of items in a warning letter from 2008.

Deficiencies identified in the warning letter include but aren’t limited to:

  • The firm failed to submit a report within ten days to report initiating a correction or removal of a device as required by the regulations.

  • The firm did not follow its own CAPA procedure with regard to complaints. FDA identified this as a repeat deficiency from the warning letter issued in 2008. 

  • The firm did not document design inputs, outputs, verification, validation and design reviews as required by their own procedure.

  • Design changes were not documented as required by the firm’s SOP, again a repeat from an item identified in the 2008 warning letter.

  • The firm has not established adequate detailed manufacturing instructions. Again a repeat from 2008.

  • The firm does not have procedures for acceptance activities to support purchased materials.

The firm also does not have a procedure for rework, yet the firm has reworked devices.

Manufacturers of Antibody Tests

FDA issued three warning letters to firms that marketed antibody tests for COVID-19 deeming the tests to be both adulterated and misbranded. The firms sold antibody tests in the US that did not have either marketing approval (PMAs), clearance (510k), or authorization (probably EAU in this case) from FDA. We will likely see more of these in the future. FDA states “When tests are marketed inappropriately, with inaccurate or misleading claims – such as the ability to perform the test completely at home, or that the test is authorized, cleared, or approved when it is not – they put the health of Americans at risk. Such conduct will not be tolerated by the FDA, and we will continue to monitor tests marketed in the U.S., taking appropriate action as warranted.” 

The warning letters were sent to the following firms:

Letters to Compounding Pharmacies and Outsourcing Facilities

The Compounding Pharmacy 

The Compounding Pharmacy (Hickory, NC) received a warning letter on June 5, 2020, based on the outcome of an inspection ending April 8, 2019. YES, OVER A YEAR AGO. As well as adulterated products, the warning letter that the ineligible drug product that the firm compounds are deemed misbranded. 

CMC Enterprise Pharmacy

CMC Enterprise Pharmacy (Charlotte, NC) received a warning letter on June 4, 2020, based on the outcome of an inspection ending March 22, 2019.  The firm has ceased the manufacture of sterile drug products.

BIMO, GCP and GLP Warning and Untitled Letters

No letters were issued this week. 

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