Data integrity violations are not subsiding anytime soon. With the US Food and Drug Administration (FDA) sharing regulatory action taken post inspections conducted in the second half of 2016, it became apparent that we will be seeing more data integrity violations in the months to come.
This week, we bring you data integrity violations that took place in India, China and Japan. In India, an oral solid dose manufacturing facility of Hetero Labs Limited in Hyderabad received a 13-page observation, known as FDA Form 483. It is issued after an inspection, when the investigators observe any objectionable condition that violates the US Food Drug and Cosmetic (FD&C) Act and other regulations.
We bring you key observations in the Form 483 to Hetero Labs, which also indicates how data integrity problems continue to exist and how investigators are finding new strategies to uncover them.
Document shredding caught on camera at Hetero labs
The inspection at Hetero Labs was conducted between December 7 and 16, 2016. Hetero Drugs is a privately held Indian pharmaceutical company with 2015 revenues estimated to be US $ 1.9 billion. Here are some key observations at Hetero:
— Destruction and alteration of records: When the investigators reviewed Hetero’s closed circuit TV, it identified a document shredder that had been introduced into the firm’s document storage area around four days before the FDA inspection. The documents being shredded were of a color consistent with batch packaging records and batch manufacturing records.
“After introduction of the document shredder, we observed extensive shredding of what appears to be controlled documents and extensive signing of documents by Quality Assurance (QA),” the investigators observed.
— Inconsistent data: 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.
— Failure to remove defective product from the market: 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.
— Unsuitable equipment: The equipment and utensils at the site were found to be unsuitable for the manufacture of drug products. 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 is no mention of deleted results on the Quality Control’s high performance liquid chromatography (HPLC) system.
However, the FDA investigators have found over 400 occurrences of a user abort since September 23, 2016. The majority of these user aborts were during data acquisition. On further investigation, the investigators uncovered that “a sub-set of these users abort events demonstrated a time gap between the last injection (analytical testing) and the user abort event.”
China’s Suzhou had no quality unit, as salespeople filled in for chemists
A warning letter issued to China-based Suzhou Pharmaceutical Technology was posted on the FDA website, and it explained why the firm had been put on import alert in October 2016.
The letter states that during an inspection conducted between June 6 and 8, 2016, investigators found the firm had no Quality Unit or written procedures for quality activities.
Moreover, the firm omitted the name and address of the original API manufacturer on the certificates of analysis (CoA) which were issued to customers, and did not include copies of the original batch certificate.
What’s worse, Suzhou’s salespeople signed the CoA under the title ‘QC Director’, and without performing tests. The sales people also signed under ‘Tested By’.
During the inspection, the facility’s room temperature was warm and humid, with no temperature and humidity control system. The facility had to open the windows in order to lower the temperature.
One of the Suzhou’s suppliers, was on the FDA Import Alert 66-40 from March 2014 to July 2016. However, Suzhou shipped API manufactured by this firm in May 2015 to the US.
integrity problems emerge in
The FDA’s observations in a warning letter to Japan’s Sato Yakuhin Kogyo pale in comparison to the observations made in the case of Hetero and Suzhou. However, data integrity concerns were cited here as well.
Sato Yakuhin Kogyo — a leading Japanese contract manufacturer — was inspected from June 6 to 10, 2016. Sato counts most major Japanese pharmaceutical companies as its business partners. The FDA observed significant violations of current good manufacturing practice (cGMP) regulations for finished pharmaceuticals.
Investigators reviewed the audit trails of Sato Kogyo’s HPLC system for impurity testing and found that the testing had been performed in duplicate. None of the chromatograms generated in the first sequence were maintained and available for review. Only the second set of chromatograms was maintained and relied upon to release the batch for use in the manufacture of products for the US market.
“Your analysts told our investigator that until June 1, 2016, they were permitted to perform repeat testing without scientific justification or documentation. They also told our investigator that they were not required to maintain the data from the original results when performing investigations of system suitability failures, suspected errors, or out-of-trend results,” the FDA warning letter said.
Over the last eight years, the FDA has nearly doubled the number of annual foreign plant inspections it conducts, observes a new Government Accountability Office (GAO) report.
The same report cites that since the beginning of fiscal year 2015, the FDA has been conducting more foreign than domestic inspections.
India and China have had the largest numbers of inspections and also the most instances of non-compliance.
With 40 percent generic drugs and 80 percent APIs coming from foreign countries, a ‘Make in America’ rhetoric, and the number of uninspected establishments at almost 1,000 of the approximately 3,000 foreign establishments, which the FDA plans to inspect over the next three years, manufacturing compliance will continue to be a focus area in the times to come.