Warning Letters Week of 3/1/2020: Device Design Controls

Enforcement this week included a collection of warning letters including three device warning letters and three drug GMP warning letters, including one to a fertility clinic governed under 21 CFR 1271. As with most warning letters in this product class, lack of adequate donor screening for the infectious disease was a prominent deficiency. We also see CDRH appearing to post a backlog of warning letters that were sent to firms at the end of 2019.

Cipla reported to the Bombay Stock Exchange that they received a warning letter based on a September 2019 inspection by FDA. The form 483 with 12 observations was 38 pages long, generally the type of form 483 that doesn’t have a happy ending for the recipient. The three investigators included Thomas Arista.

Also, note that it’s becoming more frequent for the FDA to fault the firm when they do not include interim controls when a final corrective and preventive action cannot be implemented immediately.

And finally, warning letters to firms touting treatments for the coronavirus disease finally started appearing. FDA posted seven of these on March 6 citing unapproved products, though some cite misbranding.  Five letters were issued by CDER and two were issued by CFSAN. There will be more, I’m sure.

DEVICE | ITL Asia Pacific Sdn Bhd

ITL Asia Pacific Sdn Bhd (Malaysia) received a warning letter on September 25, 2019, based on the outcome of an inspection ending May 30, 2019. The firm manufactures blood collection devices, including the SampLok System with Hinged Lid. FDA states they are taking steps to implement an import alert, but none were identified as being implemented.

Deficiencies include but are not limited to:

• The product has not yet been through the design control process developed at the firm. They are missing a design plan, design review, design verification, design validation, and design transfer.
• The CAPA procedure does not identify all quality data sources to be considered in the identification of quality problems. 
• The firm has not validated steps in the manufacturing process.
• Rejected products were accepted after testing conditions were modified and the product was then accepted.
• The results of complaint investigations were not documented nor was it identified whether corrective actions were taken and whether they were effective. 
• Devices are misbranded because the firm refused to furnish material or information under MDR reporting. 

DEVICE | Silfradent Srl

Silfradent Srl (Italy) received a warning letter on October 28, 2019 based on the outcome of an inspection ending August 1, 2019.

Deficiencies include but are not limited to:

• The device has not been subjected to design controls because the design history file did not include design inputs, design outputs, design reviews, design verifications, design validation, and design transfers. The product has been shipped to the US since 2009. Personally, this raises the question of where the FDA has been relative to this firm for the past 11 years!
• Failure to establish and maintain procedures for complaint management including their investigation. At least 11 complaints between 2017 thru 2019 do not include investigations. 
• Failure to develop and implement procedures for MDR reporting.

DEVICE | Jiangsu JDC Medical Devices Co., Ltd

Jiangsu JDC Medical Devices Co., Ltd (China) received a warning letter on December 19, 2019, based on the outcome of an inspection ending September 19, 2019. The firm manufactures the Bulb Tip Yankauer and the Chemiluminated Vaginal Speculum. FDA states they are going to put these products on import alert.

Deficiencies include but are not limited to:

• The firm’s procedures regarding control of the device do not ensure that all elements of design control are addressed including, “design and development planning, design input, design output, design review, design verification, design validation, design transfer, design changes, and the design history file.” They seem to have missed it all.
• The firm has procedures that provide a high-level strategy for the manufacture of the devices but do not identify specifications, define inputs, in-process specifications, and process outputs.
• Failure to have procedures to adequately control environmental conditions.
• The firm did not have a procedure governing MDR reporting. The procedure submitted with the 483 response did not address a variety of aspects that needed to be covered.

HCT/P, BIOLOGICS | Reproductive Technologies, Inc.

Reproductive Technologies, Inc. (Berkeley, CA) received a warning letter on November 6, 2019, based on the outcome of an inspection ending August 16, 2019. The firm is governed under 21 CFR 1271. FDA notes that they identified additional deficiencies based on a review of documents collected during the inspection. The shortcomings are entirely in the area of donor qualification and testing for infectious disease.

Deficiencies include but are not limited to:

• Failure to quarantine anonymous donor semen until testing is completed.
• Failure to test anonymous donor semen for West Nile Virus using an FDA approved test at the time of donation and to retest anonymous donors six months post-donation.
• Anonymous donors with high-risk practices were deemed eligible as donors. 
• Complete donor screening for anonymous semen donors is not repeated every six months, but rather an abbreviated screening is performed.
• Questionnaires do not include all relevant communicable disease risks including Zika virus, smallpox vaccination, those who received a non-synthetic dura mater transplant, and those who are recipients of xenotransplants. 
• The firm failed to maintain procedures for all steps in testing, screening, and complying with donor eligibility requirements in 1271 Subpart C.
• FDA includes comments on the firm’s proposed corrective actions within the warning letter. FDA also reminds the firm that if they have to move any material from quarantine prior to completion of testing, they must request an exemption from the FDA.

DRUG | Acino Products LLC

Acino Products LLC (Hamilton, NJ) received a warning letter on February 10, 2020, based on the outcome of an inspection ending June 12, 2019. The firm is a contract manufacturer of OTC products. FDA identifies that similar shortcomings were identified at an inspection conducted in 2017 and, “Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.”

The FDA also recommends they employ a qualified consultant to assist them in coming into GMP compliance. The firm is also subject of a Consent Decree Agreement (June 30, 2015) for manufacturing unapproved hydrocortisone acetate suppositories, and notes, “You should ensure you are adhering to all terms of the decree.”

Deficiencies include but are not limited to:

• The investigator observed missing ceiling tiles directly above the missing tank, open hopper, and filling machine. The firm’s response was deemed inadequate because they did not provide evidence of the repairs nor did they provide a comprehensive plan to ensure the facility remains in good repair.
• The firm failed to clean and maintain non-dedicated equipment which was, “filthy and covered with residue.” Data could not be provided to support the cleaning validation of equipment. Further, the staff told the investigator they used a different cleaning agent than the one identified in the cleaning SOPs. And finally, the firm could not provide cleaning logs for manufacturing equipment. The response was deemed inadequate because the firm could not provide equipment qualification to support that a “tape and plastic wrap” contraption of sorts, controlled temperature as required. And while the firm claims they conducted cleaning validation for bisacodyl suppositories it did not provide documentation.
• The CoA was signed by the firm, yet they could not provide microbiological test results that were included on the CoA and could not explain whether samples were sent to the contract laboratory.  While the firm committed not to sign CoAs in the future without reviewing all test data, they did not, however, including how data that support the release of products will be managed and reviewed.
• “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.”

DRUG | Chemland Co., Ltd

Chemland Co., Ltd received a warning letter on February 11, 2020 based on the outcome of an inspection ending August 22, 2019. The firm manufactures OTC drugs and was placed on import alert 66-40 on December 17, 2019. The FDA also recommended that the firm hire a qualified consultant to assist them in coming into GMP compliance.

Deficiencies include but are not limited to:

• The quality unit lacked responsibility and authority. Examples provided include failure to ensure audit trails are enabled on a laboratory instrument, storage of batch records as unlocked Excel files which permit alteration, duplication, and deletion by unauthorized personnel, and analysts used excel files for documenting sample prep and final calculations and these records were not retained. The firm’s response was not adequate because it did not include interim control measures and did not assess the impact of products released without GMP data.
• OTC products are not subject to process validation, nor has the firm performed cleaning validation. Also, equipment used in the manufacture and testing of drug products was not qualified. The firm’s response was deemed inadequate because they did not address interim controls that would be implemented until the final remediation was put in place and also did not provide a detailed validation plan for processes and qualification plans for equipment.
• The firm does not have an adequate stability program. Examples include shelf life assignments based on inadequate accelerated and long-term data. Only one batch of each product was included in the studies, and accelerated studies did not include evaluation of humidity control.  Samples were not stored under conditions of controlled temperature or humidity. Stability studies did not include an evaluation of the assay.  Stability samples were not stored in containers that simulate the market container. The firm’s response was inadequate because they did not provide stability protocols and assurance that the methods used will be adequate. Further, there were no interim plans to ensure that the product shelf life is supported by adequate studies.
• “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.”

DRUG, MISBRANDING | Natures Rx LLC and Mikart LLC

Natures Rx LLC and Mikart LLC received warning letters for misbranding drugs.