We’re back after a week off and covering all warning letters from the last two weeks. Lots of reading, including more to OTC manufacturers who continue to fail to understand and implement the fundamentals of GMPs. There is also one warning letter to a cell therapy manufacturer.

Although we do not routinely cover enforcement actions by the Center of Tobacco Products, we do cover first-of-its-kind actions. Read here for more information on the recent warning letter to JUUL Labs.

In addition to the warning letters below which cover those posted on September 3 and September 10, 2019, the FTC sent warning letters to three unidentified firms selling CBD products. The firms were advertising the product(s) to treat disease, yet no scientific evidence was provided to support this claim. 

DRUGS | Yino Inc.

Yino Inc. (China) received a warning letter dated August 12, 2019 based on the outcome of an inspection ending March 22, 2019. The firm manufactures APIs including heparin and heparin products according to their website.

The firm was placed on import Alert 66-40 on August 1, 2019. FDA recommends that the firm retain qualified consultants to assist them in coming into compliance with CGMPs. FDA also notes they have not received a response to the form 483 issued at the end of the inspection. It’s interesting that they waited this long to both impose an import alert and issue a warning letter.

Deficiencies include but are not limited to:

  • The firm repackages APIs made by other manufacturers and distributes them to the US. The information regarding the name and address of the original manufacturer is omitted on the COA that the firm produces. This is yet another example of failure of re-packagers to provide complete information on the product CoA.
  • The firm does not have an adequate quality system and lacks quality oversight on documentation. The CoA issue from above is provided as an example including the information that the CoA does not include a signature and date by the responsible person in the Quality Unit.
    • “In response to this letter, provide a plan to establish, document, and implement an effective system for managing quality. Include written procedures for CGMP-related activities and the roles of personnel responsible for oversight.”

DRUGS | Haw Par Healthcare Limited

Haw Par Healthcare Limited (Singapore) received a warning letter on August 19, 2019 based on the outcome of an inspection ending March 1, 2019. This warning letter replaces one dated August 14, 2019.

The product named in the warning letter is Tiger Balm Liniment, an OTC product. FDA suggests the firm hire a qualified consultant to assist them in coming into compliance with GMPs. In addition to the CGMP violations, the firm is also cited for misbranding.

Deficiencies include but are not limited to:

  • The firm invalidated OOS rest results for an API without scientific justification. Drug product made from this lot of API was OOS for assay. The vendor provided information about problems with this lot and suggested additional processing before use. Only portions of the drug product batches were rejected rather than the entire batch.
  • The results from forced degradation studies were not used to establish stability acceptance criteria.
  • Computer systems for analytical instrumentation do not have audit trail capability including GCs, FTIR and UV / VIS spectrophotometer.
    • FDA states that “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.”
  • The water system (redaction is pretty substantial, but that’s the only thing that fits) is not adequate for its intended use. The system design has dead-legs, and flushing that occurs prior to sampling is not consistent with how the system is used.

DRUGS | Polimeros y Servicios S.A

Polimeros y Servicios S.A (Costa Rica) received a warning letter on August 22, 2019 based on the outcome of an inspection ending February 8, 2019. The firm manufactures OTC products including topical analgesics, antifungal, acne, and skin protectant creams.

The firm was placed on import alert 66-40 on July 11, 2019. FDA recommends the firm hire a qualified consultant to assist them in coming into GMP compliance. They also note that similar failures were cited in a 2017 inspection that the firm has failed to correct. And finally, the firm is distributing unapproved new drugs with inadequate labeling so the products are also misbranded.

GMP deficiencies include but are not limited to:

  • Products are not tested prior to distribution to ensure they meet appropriate standard specifications.
  • The firm failed to test incoming raw materials including APIs, but rather relied on the supplier Certificate of Analysis for release.
  • The firm does not have an adequate stability program to demonstrate that the products are stable thru the three year expiry dating.
  • The firm uses non-dedicated equipment to manufacture multiple products without validated cleaning to prevent cross contamination. Also, the cleaning protocol does not include sufficient detail to allow consistent effective cleaning.
  • The firm’s Quality System is inadequate, and FDA references the FA guidance on the topic.

DRUGS | Hangzhou Badi Daily Use Chemical Company

Hangzhou Badi Daily Use Chemical Company (Zhejiang Province, China) received a warning letter of August 29, 2019 based on the outcome of an inspection ending March 21, 2019. The firm manufactures OTC drug products and was placed on Import Alert 66-40 on July 30, 2019.

Along with the specific violations the FDA also states that products are adulterated within the definition of the FD&C Act because they are “prepared, packed, or held under insanitary conditions.” FDA notes that similar GMP violations were seen at a 2016 inspection and recommends that the firm hire a qualified consultant to assist them in their remediation program.

In addition, the firm has stated that they will cease distribution of drugs in the US. The firm also manufactures cosmetics as a CMO, and the warning letter cites violations of the FD&C Act with regard to their manufacture.

And last but not least, they are distributing unapproved new drugs that are misbranded because they do not include adequate instructions for use.

Deficiencies include but are not limited to:

  • Data to demonstrate that drug product was tested for identity and potency of the active ingredient could not be provided. Further, the FDA investigator was told that the formula did not contain the labeled active ingredient.
  • The firm failed to test incoming APIs and other components, nor could they show documentation of receipt of the labeled active ingredient. Further, FDA states that the firm manufactures drug products containing glycerin and fail to test for contaminants DEG and EG. The firm was previously implicated in DEG contamination and was placed on import alert for that reason.
  • The manufacturing process for drug products has not been validated and the firm does not have an ongoing process monitoring program to ensure the process remains under control.
  • Product expiry dating is not supported by data, and there is no stability program. The investigator was informed that the firm “lack[s] the capability to perform a stability study to assess the stability characteristics of your OTC drug products.”

DRUGS | Enprani Co., Ltd.

Enprani Co., Ltd. (Seoul, South Korea) received a warning letter dated August 15, 2019 based on the outcome of an inspection ending March 15, 2019. The firm manufactures OTC products and failed to register the establishment with FDA, and also failed to list the drugs manufactured at the facility. The firm was placed on Import Alert 66-40 on July 15, 2019. The warning letter also cites numerous concerns about product labeling, including revisions to labeling made in response to the form-483 issued at the close of inspection.

Deficiencies include but are not limited to:

  • Continuing the all too common deficiency identified at OTC product manufacturers, drug product was not tested for the identity and strength of the active ingredient. Raw data for assay, lead, and arsenic were reported to have met specs, but the data were not available for review. Staff stated they ceased testing for a redacted attribute in September 2017 because previous results were consistently passing. To resolve testing issues, the firm states they will employ a contract laboratory but the FDA deemed this response inadequate because they did not state how the contract laboratory would be qualified.
  • The quality unit lacked adequate authority and responsibility. In particular, they failed to review batch records, raw data, and calculations; batch records were pre-printed as “approved” indicating that materials met specs before the values were recorded, and label review and line clearance were not performed and documented in batch records.
    • In response to the warning letter the firm is asked to provide: “an independent comprehensive assessment with corrective and preventive actions (CAPA) to ensure your QU is given the authority and resources to effectively function.”
  • The manufacturing process for drug products is not validated and the firm does not have an ongoing process monitoring program. The firm’s response to this item on the form 483 was deemed inadequate because they did not provide a protocol and overall program description and did not conduct a risk assessment for product already distributed in the US that the firm has been unable to recall.
  • The existing stability program is inadequate to establish adequate expiry dating.
    • “In response to this letter, provide a comprehensive assessment and CAPA plan to ensure the adequacy of your stability program.”
  • The firm does not exercise adequate controls over computer systems. For example, laboratory analysts have access to HPLC instruments that allow them to overwrite, delete, copy, and rename raw data. Further, audit trails are turned off so they are not available during data review.
    • “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.”

HUMAN CELL/TISSUE | Stemell Inc.

Stemell Inc. (San Juan Capistrano, CA) received a warning letter on August 28, 2019 based on the outcome of an inspection ending March 8, 2019. The firm manufactures products derived from human umbilical cord blood and umbilical cord.

This firm tries to circumvent the need for product approval with a variety of disclaimers. This approach didn’t satisfy FDA. Stemell also did not qualify for any exception to 21CFR 1271.15, nor are the products for autologous use. The warning letter includes a LONG section on why FDA has authority in this area and why they are citing the firm in a warning letter. They also cite the firm for using the FDA logo on their website which may violate federal law.

Deficiencies include but are not limited to:

  • Donor eligibility determinations are not documented.
  • The firm did not establish and maintain procedures for determining donor eligibility.
  • Aseptic processes have not been validated even though the products purport to be sterile and are expected to be sterile. Four examples of shortcomings are provided.
  • EM is deficient because alert and action limits have not been established. The cleaning and disinfection of Class 100 processing area and equipment are not in writing and have not been validated.
  • Non-sterile disinfectants and non-sterile wipes are used for room/area cleaning and there is no evidence that a sporicidal agent is used.
  • No written procedures describe the approval or rejection of incoming umbilical cord blood or umbilical cord.
  • Specifications for product have not been established.
  • Expiry dating of one year is not supported by data.
  • Cold storage units are not supported by temperature records retained by the firm.
  • No procedure for management of complaints has been developed.
  • There is no quality unit.

INVESTIGATOR/SPONSOR | Balamaurali K Ambati MD Ph.D.

Balamaurali K Ambati MD Ph.D. (Eugene, Oregon) received a warning letter on August 13, 2019 based on the outcome of a BIMO inspection ending April 4, 2019. Dr. Ambati was a sponsor-investigator of an investigational drug.  The single deficiency included but was not limited to:

  • Dr. Ambati did not file an IND for the conduct of the clinical investigation study that he conducted.  The investigational material did not qualify from exemption to submit an IND. Subsequent to the inspection, an IND was submitted.

COMPOUNDING PHARMACY/OUTSOURCING FACILITY | Sharp Drugs, Inc dba Island Drug and Surgical

Sharp Drugs, Inc dba Island Drug and Surgical (West Hampton Beach, NY) received a warning letter on August 2, 2019 based on the outcome of an inspection ending July 13, 2018.