After three weeks of no warning letters, this week the FDA posted five drug GMP warning letters and three device GMP warning letters. We cover them all below.

In addition, enforcement actions for failure to comply with the Foreign [Food] Supplier Program are in full swing. Another two warning letters were posted this week, totaling three FSVP warning letters issued so far this year. Last year saw a total of six issued FSVP warning letters.

OUTSOURCING | LeeSar Inc

LeeSar Inc (Fort Myers, FL) received a warning letter on February 18, 2020 based on the outcome of an inspection ending July 12, 2017 (no, not a typo). The firm is an outsourcing facility. The firm is compounding drugs that do not qualify for exemptions under section 503B.

Also, the drugs are misbranded because they are not “intended for conditions amenable to self-diagnosis and treatment by individuals who are not medical practitioners” and do not have accompanying instructions for use to ensure a layperson can use them correctly.

DRUGS | Essnd Global

Essnd Global (Mumbai, India) received a warning letter on February 14, 2020 based on the outcome of an inspection ending September 13, 2019. The firm has not yet responded to the Form 483. They contract manufacture OTC products and they were placed on Import Alert 66-40 on January 31, 2020. FDA reminds them of their responsibilities as a contractor.

Further, FDA suggests they employ a qualified consultant to assist them in coming into GMP compliance. This warning letter continues with the now all too familiar list of deficiencies that OTC manufacturers have become known for.

Deficiencies include but are not limited to:

The firm fails to test drug product for identity and strength of the active ingredient before product release for distribution.
The firm did not test incoming components including active ingredient for identity and other appropriate attributes. “Furthermore, you informed our investigator that your clients can send the raw materials, the labeling, and packaging materials without the Certificates of Analysis (COA) to your facility.” That approach was not successful.
The water system (they missed one redaction that makes this clear) is not adequately monitored and alert and action limits may not be appropriately stringent for antiseptic products.
The firm lacks an adequate Quality Unit and told the FDA investigator that they had not fully established a Quality Unit. In addition, they lack basic SOPs for Quality functions including stability, OOS investigations, product release, and deviation investigations. FDA stated “Your firm’s quality systems are inadequate.”

DRUGS | Yibin Lihao Bio-technical Co., Ltd

Yibin Lihao Bio-technical Co., Ltd (China) received a warning letter on February 13, 2020 based on the outcome of an inspection ending August 6, 2019. The firm manufactures crude heparin that will be used to manufacture heparin API. The firm was placed on two Import Alerts, 66-40 and 55-03 on January 15, 2020.

FDA encourages the firm to hire a qualified consultant to assist them in coming into GMP compliance. Deficiencies center on the falsehoods that were communicated to FDA investigators, lack of documentation supporting the crude heparin manufacture and testing, and lack of control over critical documentation associated with the manufacture of crude heparin.

An inspection by the Italian authorities on October 31, 2018 resulted in a report of GMP non-compliance for the same operation. The nature of the non-compliance included “24 GMP deficiencies, of which 7 were categorised as major. The major deficiencies were found in the following areas: 1. Risk of contamination; 2. Buildings and facilities; 3. Equipment; 4. Storage of starting material; 5. Process; 6. Materials management, traceability of starting material; 7. Recovery of solvents.”

Deficiencies in the warning letter include but are not limited to:

In a pre-inspection phone call, the firm told FDA they had not manufactured crude heparin product for months. When FDA arrived on site and walked through the warehouse, they saw an employee leave the warehouse with a fiber drum. Investigators asked about the contents of the drum and were told it contained [redacted] bags. However, inspection of the contents of the fiber drum revelated crude heparin manufactured a few days prior to FDA’s arrival. When asked for records supporting manufacture and testing of this material, the firm stated they did not have records. The firm’s response to FDA was inadequate because they did not explain how they would remediate the poor documentation practices and they did not commit to assess the impact of the poor documentation practices on product already in distribution.
The firm did not provide adequate control over critical GMP records relative to the traceability of the crude heparin manufactured at the facility. Investigators observed records on the floor, desks and cabinets of the QA office. “During the inspection, one of your employees stated that these records were generated to support an application for government funding, but the crude heparin batches specified in the records had not actually been manufactured. However, later during the inspection, on August 2, 2019, your firm stated that all the records in the QA Office were in fact associated with genuine crude heparin batches.” The firm’s response to the observation was inadequate because it did not take a holistic approach to resolving Quality Unit deficiencies.
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.”

DRUGS | JHS Svendgaard Hygiene Products Ltd

JHS Svendgaard Hygiene Products Ltd (India) received a warning letter on February 13, 2020 based on the outcome of an inspection ending August 22, 2019. The firm manufactures OTC products and was placed on Import Alert 66-40 on January 2, 2020. FDA also recommends the firm hire a qualified consultant to assist them in coming into GMP compliance.

Deficiencies include but are not limited to:

The firm relied on the CoAs provided by non-qualified suppliers rather than performing identity testing and evaluation of other quality attributes. They also did not confirm the reliability of the vendors’ analyses through validation. Their response was deemed inadequate because their procedure for supplier qualification wasn’t specific enough and the SOP for validation of analytical results lacked specificity. And finally, it did not include a retrospective evaluation of products already in distribution with raw materials that were not adequately tested or qualified.
The firm lacked analytical method validation (or qualification of USP methods) used in lot release testing. The firm also failed to conduct identity testing of the drug product. The firm’s response was deemed inadequate because the firm did not provide adequate evidence of validation or verification and the timeframe for completion.
The firm did not follow written procedures for process validation and did not have an ongoing program of process monitoring. Also, the firm did not validate current cleaning procedures. The response indicated process and cleaning would be re-validated which is in conflict with what the investigators were told during the inspections…that processes and cleaning have not been validated. FDA asks them to explain how re-validation of processes that were never validated could be conducted. The response also lacked detail on the planned validation activity including draft protocols. Finally, the response did not address the effect that lack of validation may have on distributed product within expiry.
The Quality Unit was inadequate. For example, they did not report and investigate deviations that could have impact on final product, including changes made to process parameters in batch records that were outside the established limits for speed and temperature. The Quality Unit did not ensure the appropriate batches were placed on stability.

DRUGS | KVK-Tech, Inc

KVK-Tech, Inc (Newton PA) received a warning letter on February 11, 2020 based on the outcome of an inspection ending April 16, 2019. The firm is a drug product manufacturer.

Deficiencies include but are not limited to:

The firm self-identified failure to properly integrate co-eluting peaks during impurity testing in 2016. As a result, at least one OOS was not identified. The firm conducted additional training as a result, but in at least one case an analyst continued to perform the incorrect integration which was not detected by the QC reviewer. The lot would have been OOS but remained on the market because this wasn’t identified. FDA noted they saw multiple examples of failure to correctly integrate closely eluting peaks. FDA found the response and new procedure inadequate because it included incorrect integration parameters that would result in under-reporting of impurities. Of particular concern is that this was reviewed and approved by the Quality Unit.
The firm failed to adequately investigate foreign particles in a lot of oral solution during the filling process. The firm filtered out the particles, performed a visual inspection and released the lot without determining the nature of the particle and its potential impact on drug quality. As a result of the inspection, the firm recalled that lot of product. In response to the 483, however, they did not commit to conducting a review of all similar manufacturing events.
Access to computer systems is not adequately controlled. Analysts have operator privileges. Data files can be overwritten or modified without being captured on some instruments including the FTIR and spectrophotometer. A previous inspection identified a similar shortcoming with some equipment but the firm failed to take a comprehensive approach to extending the corrective actions to other laboratory equipment.

DEVICE | Biomedix WAI

Biomedix WAI (Bloomington, IN) received a warning letter on February 12, 2020 based on the outcome of an inspection ending October 31, 2019. The firm manufactures IV Administration Sets and Extension Sets.

Deficiencies include but aren’t limited to:

The firm did not establish and follow adequate procedures for dealing with non-conforming material. Among the issues are 233 instances of documented tests with anomalous or failed test results not identified and investigated. There is a long litany of examples here and the firm failed to commit to a retrospective review of DHRs to ensure all such events are identified.
Failure to adequately ensure processes are validated. This is a repeat observation from a warning letter from 2013.
Failure to establish and maintain procedures for monitoring and control of process parameters for validated processes. This is a repeat observation from a regulatory meeting held in 2018.
Failure to establish and maintain acceptance procedures to ensure requirements for in-process product are met. For example, during the inspection, the investigators noted that equipment settings were not verified prior to use as required by the firm’s SOP.
Changes impacting device design are not verified or validated prior to implementation.

DEVICE | Unetixs Vascular, Inc.

Unetixs Vascular, Inc. (North Kingstown, RI) received a warning letter on February 4, 2020 based on the outcome of an inspection ending October 29, 2019. The firm manufactures vascular diagnostic ultrasound systems.

Deficiencies include but are not limited to:

The firm failed to establish: a design and development plan, design inputs, design outputs, and failed to review and validate the design.
The firm failed to monitor production processes to ensure a device conforms to specifications.
Failure to maintain procedures for acceptance criteria. This is a repeat deficiency identified in the 2017 warning letter.
The firm failed to establish and maintain procedures for CAPA. This is also a repeat deficiency identified in the 2017 warning letter.
Nine of the 20 complaints reviewed were not investigated properly or the documentation for not investigation was inadequate. Again, a repeat from the 2017 warning letter.

DEVICE | CPAPNEA Medical Supply

CPAPNEA Medical Supply (Phoenix, AZ) received a warning letter on January 22, 2020 based on the review of the firm’s website and an inspection ending July 30, 2019. The firm has a cleared 510(k) for a single indication of alleviating snoring during sleep in adults.

The firm’s labeling for the device indicates it is intended to treat obstructive sleep apnea and that it may substitute for CPAP devices which is beyond the cleared indications for use. As such the device is misbranded. The remainder of the deficiencies identify an almost total lack of SOPs for basic processes.

The deficiencies include but are not limited to:

The firm has not established CAPA procedures.
The firm has not established procedures for complaint management.
The firm has not established procedures for acceptance activities.
The firm has not established procedures to ensure that all purchased products and services conform to specifications.
The firm has not established procedures for conducting internal quality audits.
The firm has not established procedures to ensure that device history records are adequately maintained and are in compliance with the device master record. Of particular concern is that approximately 600 units of the device have been manufactured since January 2019 and there are no DHRs for these activities.
The firm has not established procedure to ensure that MDR reporting is performed as necessary.
The firm has not established procedures for transmission of complete medical device reports.