In March 2017, PharmaCompass had shared the observations made by the US Food and Drug Administration (FDA) investigators — Latorie S. Jones and Massoud Motamed. The duo had spent 10 days at the finished formulations facility of Hetero Labs in Hyderabad (India), where they .
This month, the FDA issued a warning letter to Hetero Labs where it cited concerns over the quality of the products being supplied by Hetero to the United States. The warning letter highlights that investigations into process deviations and out-of-specification (OOS) laboratory results were insufficient, and did not include scientifically supported conclusions.
In response to the warning letter, the FDA wants to see a detailed retrospective review of all complaints, manufacturing, and laboratory investigations associated with each product that Hetero Labs produces for the US market.
The FDA also wants Hetero to review all manufacturing process validations for each product that can be exported to the US, to ensure Hetero’s manufacturing processes are capable of consistently yielding finished products that meet quality attributes and manufacturing requirements.
The warning letter also mentions the investigators’ concerns over the cleanliness of the equipment. However, surprisingly, there is no mention in the warning letter about data integrity concerns.
Concerns raised in Form 483 issued to Hetero
According to the Form 483 issued to the Hetero site in March this year, a document shredder had been introduced into the firm’s document storage area around four days prior to the FDA inspection. The documents being shredded were of a color consistent with the batch packaging records and batch manufacturing records.
In addition, data derived from the company’s programmable logic controller (PLC) for compression machines was found to be inconsistent with batch records and validation reports in support of applications to the FDA.
Hetero Labs received a complaint as “one tablet in bottle was twice the thickness” of others, with the same markings and color as the other tablets.
The firm then conducted an investigation and confirmed this weight disparity, following which it concluded that if the patient inadvertently consumes the tablet (which was twice the thickness/weight), there would be “no impact” on the patient’s health or safety. The firm failed to remove the defective product from the market.
Deficiencies in the quality of equipment and utensils used at the site were also mentioned in the Form 483 issued as investigators found residue on equipment which was stated to have been “cleaned”. The product transfer lines were soiled and had a mold like appearance.
Unlike other companies where data-integrity violations are an outcome of disabled audit trails or deleted test results, at Hetero the audit trail was enabled and there was no mention of deleted results on the Quality Control’s high performance liquid chromatography (HPLC) system.
However, the FDA investigators did find over 400 occurrences of a user abort since September 23, 2016, the inspection started on December 7, 2016. Majority of these user aborts were during data acquisition. On further investigation, investigators uncovered that “a subset of these user abort events demonstrated a time gap between the last injection (analytical testing) and the user abort event.”
Non-compliance at Bristol Labs, UK
While the FDA’s warning letter had no mention of data integrity concerns at Hetero in India, the UK regulator — Medicines and Healthcare products Regulatory Agency (MHRA) — issued a statement of non-compliance to Bristol Laboratories, a finished formulations manufacturer based in the UK.
Headquartered in Hertfordshire (the UK), Bristol Laboratories is a pharmaceutical company engaged in the development, manufacture, marketing and distribution of generic medicines in the UK and Europe.
In a July 2017 inspection, the regulator identified two critical deficiencies “relating to the integrity and recording of GMP critical data and with the ongoing stability monitoring program”. The regulator has recommended the withdrawal of the GMP certificate (previously issued to the site) and has prohibited supply of non-critical products to the European Union.
From January to July, the FDA issued 265 warning letters to companies, notifying them of what it alleged to be serious violations of federal rules. According to a review of letters posted on the FDA’s website, this is the lowest tally for the first seven months of any year since 2008.
When compared with the number of warning letters issued during all the eight years of Barack Obama’s presidency, this marks (on an average) a 30 percent decline.
While Donald Trump was sworn in as the President of the United States in January this year and Scott Gottlieb became FDA’s new commissioner four months later, it remains to be seen if this drop in warning letters being issued is a new policy or a sheer coincidence.
The warning letter issued to Hetero, which is devoid of any data integrity concerns, makes one wonder if there is more to it than just a coincidence.