FDA posted three drug GMP warning letters this week to pharmaceutical firms, one to a compounding pharmacy, one to a GLP site, and two to device manufacturers. CDRH appears to have come alive again after a very slow 2019.

Regarding the device warning letters, several were posted on the FDA site for an hour or so, and dated April 7 (I don’t know why they would pre-date this, that’s a longer discussion about data integrity). I was able to grab a couple before they were taken down, hopefully, the others will appear next week with the correct date, or at least not be pre-dated again.

And finally, the FDA continues to issue warning letters to firms that are distributing unapproved products to treat COVID-19 disease.

DRUGS | Ficosota LTD (Bulgaria)

The firm received a warning letter on February 28, 2020, based on the outcome of an inspection ending September 5, 2019. FDA placed the OTC firm on Import Alert 66-40 on January 10, 2020. FDA also recommended that the firm hire a qualified consultant to assist them in coming into CGMP compliance. Even with a consultant, FDA notes that “Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.”

The firm’s quality systems are deemed to be inadequate and they lack an ongoing program for monitoring processes to ensure they remain in a state of control. Overall the FDA deemed the firm’s response to be inadequate because it did not include any details on corrective actions nor did it include analysis of the effect the identified deficiencies may have on a product already distributed in the US. This latter shortcoming is one that is almost becoming boilerplate in recent warning letters.

Deficiencies include but aren’t limited to:

  • The firm failed to perform appropriate QC testing prior to the distribution of products to the US market. This includes identity and strength testing for the active ingredient in the drug product.
  • The firm failed to test incoming raw materials including API, but rather accepted results on the certificate of analysis. Further, the suppliers were not qualified and the firm did not confirm the reliability of the results on the CoA, either initially or on a periodic basis.
  • The Quality Unit is inadequate and has failed to perform basic responsibilities including failure to approve and reject API and drug products; ensure testing is performed and reviewed prior to batch release; failure to review and approve MBRs and PBRs and ensure they included sufficient detail.
  • The stability program does not require long term evaluation for the drug product. The expiry date was 3 years even though the stability program did not include adequate physicochemical and microbiological attribute evaluations to justify that dating. The firm could only provide limited data to support the 3-year expiry.

DRUGS | Trilogy Laboratories, LLC (Fort Myers, FL)

Trilogy Laboratories, LLC received a warning letter on March 5, 2020, based on the outcome of an inspection ending August 27, 2019. The firm “manufactures, repackages, distributes or sells” sunscreens and other products which appear to be in the cosmetics and OTC category.

The firm’s response to the form 483 was inadequate and did not include an evaluation of the impact of the deficiencies on the product currently on the market and within expiry. The warning letter included three GMP deficiencies along with a litany of “unapproved new drug” and “misbranding” violations. The firm has ceased production at this facility and FDA advises them they need to notify FDA prior to re-starting production.

Deficiencies include but aren’t limited to:

  • The firm does not perform adequate tests of drug product prior to release including, but not limited to, identity and strength testing for APIs.
  • The firm did not validate the vendor CoA results at periodic intervals and did not identity test each component upon receipt.
  • The firm has not established and implemented adequate procedures to ensure that products have the identity, strength, quality, and purity they are represented to have. 

DRUGS | Pfizer Healthcare India Private Limited (Visakhapatnam, India)

The Chairman and CEO of Pfizer, based in NY, received a warning letter on March 25, 2020, based on the outcome of an inspection at a sterile injectable drug manufacturing site in India ending September 6, 2019.  This site was a part of the Hospira acquisition several years ago. These sites have proven to be nothing but an ongoing headache for Pfizer with remediation that just never seems to adequately take hold and warning letters that continue to be issued. 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.” FDA acknowledged the firm is hiring a consultant to audit their operations and assist in meeting GMP requirements.

Deficiencies include but aren’t limited to:

  • The firm failed to conduct adequate investigations and implement effective CAPA actions. The deficiency focused on two areas: sterility failures and the environmental monitoring program.
    • Regarding the sterility failures, it appears there may have been due to a “lack of robust [container closure] integrity testing and possible non-integral drug product vials.” Corrective changes were not implemented until several lots later. The firm committed to inspecting sterility test samples for integrity prior to testing. FDA felt that other corrective actions were not timely in its implementation. Further, the response to the form 483 did not include the revised investigation and the status of progress on the corrective and preventive actions.
    • Regarding the environmental monitoring program, the firm did not adequately investigate shortcomings in the microbiology laboratory conditions and practices. Common problems included an excessive number of negative control plate contamination, EM data that were not considered because of delays in reading the plates, and high levels of contamination in EM samples for sterility tests. The firm also did not have documentation of earlier readings performed before the extended incubation times. FDA noted that lab data accuracy was a deficiency cited in an inspection from September 2018, thus this is a repeat deficiency. This seems like a laboratory that is not operating in a state of control.

GLP (Pre-clinical Animal Studies) | Steiner Biotechnology LLC (Henderson, NV)

Steiner Biotechnology received a warning letter on February 3, 2020, based on the outcome of a BIMO inspection ending June 28, 2019. The inspection was conducted regarding their activities supporting the Skeletal Graft and Ridge Graft devices. No mention is made of the sponsor.

Deficiencies include but aren’t limited to:

  • Studies were not conducted consistent with protocols.
  • Multiple surgeries were conducted on animals yet none of the protocols called for this. Some animals were used in multiple studies, though the study protocol states that animals will not be used in multiple studies. The firm provided a justification for this practice but the FDA did not accept their reasons and provided a detailed explanation for rejecting this response.
  • Anesthesia used in the surgeries was not the one specified in the protocol. The firm’s response that their research veterinarian deemed the anesthesias adequate was not accepted by the FDA along with FDA’s reasons.
  • The Quality Unit failed to meet its responsibilities as described in 21CFR5835(b)(3) and (c). Checklists that were used during periodic evaluation by the Quality Unit were inadequate and did not identify all activities that should be considered. Further, the firm did not have written documentation of the responsibilities and procedures for the Quality Unit.
  • Specimens collected were not properly labeled as specified in the regulations. Two were labeled only with an animal number written on the side of the container or the lid, and in other cases, several samples were located in the same container without appropriate identification.  While the firm committed to correctly identify samples, they did not address how this violation would be prevented in the future.
  • The FDA investigator was unable to obtain complete and current training records for staff who participated in the studies in question.  

DEVICES | E-Care Technology Corp (Taiwan)

E-Care Technology Corp received a warning letter on March 2, 2020, based on the outcome of an inspection ending October 25, 2019.

Deficiencies include but aren’t limited to:

  • The firm did not document design configurations used in the testing of the devices. Further, the report issued for this component of design control validation did not include the lot number or other means to identify the device(s) used in the validation study.
  • Inspection, measuring, and test equipment are not demonstrated to be suitable for its intended use and to generate valid results.
  • The firm does not have a means of receiving complaints regarding products sold in the US by private-label customer(s).
  • The firm has not ensured that sampling methods are adequate and reviewed when changes occur.

DEVICES | Okamoto Rubber Products Co., Ltd. (Thailand)

Okamoto Rubber Products Co., Ltd received a warning letter on February 14, 2020, based on the outcome of an inspection ending November 7, 2019.  The firm manufactures lubricated natural rubber condoms.

Deficiencies include but aren’t limited to:

  • The firm has not validated the rework process permitted in their procedures.
  • CAPA procedure(s) have not been adequately developed, maintained and followed.
  • Sampling methods are not demonstrated to be adequate for their intended use.

HCT/P | Dynamic Stem Cell Therapy (Henderson, NV)

Dynamic Stem Cell Therapy received an untitled letter on April 1, 2020, based on the review of their website and Facebook page. They market cellular products that are advertised to treat a range of medical conditions including COVID-19 infections. Likely, that may be how they caught the FDA’s attention. This untitled letter was not based on an inspection of their manufacturing or clinical site.

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