In October 2016, the US Food and Drug Administration (FDA) inspected a facility in India belonging to Granules India that manufactures pharmaceutical formulation intermediates (PFIs) and finished dosage forms (FDFs). The FDA had no observations.
Three months later, Portugal’s health authority — INFARMED — inspected the same site and detected non-conformities in good manufacturing practices (GMPs).
According to an alert published on the INFARMED website, the observations were related to granulation and primary packaging of tablets in batches of drugs related to paracetamol and metformin supplied by Granules to Mylan, Bluepharma and Sandoz. The agency recommended the suspension and recall of certain batches from the market in Portugal.
Last week, based on “General GMP Observations” of “regulatory partner(s)”, Health Canada placed Granules India’s facility located in Gagillapur (near Hyderabad) on its inspection tracker. Health Canada’s inspection tracker provides updates on the actions the regulator is undertaking to assess and manage potential risks arising from inspections of drug manufacturing facilities.
According to Granules, their facility in Gagillapur contributes over 50 percent to their revenues and “has the world’s largest PFI capacity along with an industry-leading batch size of six tons. In addition, the Gagillapur facility has one of the largest single-site finished dosage capacities in the world for their respective products.”
In a recent interview, C. Krishna Prasad, managing director of Granules India, said there were no issues related to data integrity and INFARMED is scheduled to re-inspect the Gagillapur facility this week.
Data
integrity concerns at ACS Dobfar’s
Italian facility
The FDA’s April 2016 inspection of ACS Dobfar’s operations in Brazil — Antibioticos do Brasil (ABL) — led to the issuance of a warning letter in December. Among other observations, the FDA investigators found that the filling zone for sterile injectable product was not sufficiently robust. Therefore, it didn’t protect the drugs being manufactured there (such as during the times when operators entered the final filling area).
Almost immediately after the warning letter was issued, an inspection of the same facility by the Italian Regulatory Agency (AIFA) found it not-compliant for the manufacture of the active ingredient — Cephalexin Sodium Sterile. AIFA also recommended the suspension of the Certificate of Suitability issued for ceftazidime pentahydrate with sodium carbonate for injection.
The inspectors found ABL failed to ensure a good level of maintenance and cleaning of the final crystallization area and there was a poor level of training, low knowledge and awareness of good manufacturing practices (GMP) along with lack of supervisory control.
The non-compliance report also mentions that some non-authorized and fraudulent activities were stopped before inspectors entered certain manufacturing areas.
Fraudulent activities were not limited to Brazil, as ACS Dobfar’s Italian drug manufacturing facility — FACTA Farmaceutici SpA — had FDA investigators uncover data-integrity violations during a January 2016 inspection.
The warning letter issued to FACTA mentions that for multiple lots of sterile drug product, where the original data showed failing results, the data reportedly showed passing results.
The company was found storing original data in an “unofficial” and uncontrolled electronic spreadsheet on a shared computer network drive. The analyst told investigators that original data was first recorded in the “unofficial” spreadsheet and later transcribed to an “official” form.
Investigators also observed many copies of uncontrolled blank and partially-completed cGMP forms and also documented that employees at FACTA used paper shredders to destroy critical laboratory and production records.
It is worth mentioning that FACTA’s EU GMP certification was renewed by the Italian regulators after an inspection that was conducted at the same time as the FDA inspection.
Data integrity concerns confirmed at Divi’s Laboratories in India
Divi’s Laboratories’ Unit-II situated in Visakhapatnam, Andhra Pradesh — one of the biggest manufacturing facilities for the major producer of active pharmaceutical ingredients (APIs) — was inspected by the US FDA from November 29 to December 6, 2016.
The regulators issued a Form 483 with five observations. While data integrity concerns had been widely reported in news media, Health Canada confirmed the violations by placing the company on its inspection tracker last week.
FDA’s warning letter comes to haunt Dr. Reddy’s
South Korean biotech firm — Mezzion Inc — filed a suit for damages against Dr. Reddy’s in New Jersey state court alleging that it hid “significant deficiencies in its FDA cGMP practices” and misrepresented its compliance.
Mezzion has stated in its suit that “Dr. Reddy's repeatedly represented to Mezzion that it was compliant with FDA regulations” whereas the FDA issued a warning letter to Dr. Reddy's.
During an FDA inspection at Dr. Reddy's facilities in India, the FDA identified numerous data integrity violations and also uncovered a previously unknown and uncontrolled “Custom QC laboratory” (CQC), which engaged in a “practice of substituting repeat tests after failing results.”
Mezzion further states: “Dr. Reddy’s misconduct was the sole reason given by the FDA to deny approval of Mezzion’s new drug application (NDA) for udenafil for the treatment of erectile dysfunction (ED)”. As a result, Mezzion has incurred delays and was forced to seek new manufacturers and suppliers for udenafil and the udenafil finished product, in order to resubmit its udenafil New Drug Application (NDA) to the FDA for approval.
FDA’s warning letters to
manufacturers in UK and India
Porton Biopharma, UK: A warning letter was issued to the UK-based Porton Biopharma by the US FDA for manufacturing violations related to Erwinaze (asparaginase Erwinia chrysanthemi) — an orphan biologic which was developed by Porton and licensed to Jazz Pharmaceuticals.
According to the warning letter, the FDA had previously performed an inspection of Porton’s facility in January 2015 and found similar concerns. The inspection between March 7 and 18, 2016, which triggered the warning letter, had FDA investigators observe continued deficiencies, including metal particles which penetrated a few batches of Erwinaze, another batch containing paper or cardboard fibers and a possible microbial contamination.
While Porton believed that vial stoppers were the source of the metal scraps, the FDA investigators were not convinced.
Erwinaze generated around US $ 43 million in the third quarter for Jazz Pharmaceuticals, accounting for more than 10 percent of the company’s revenues.
CTX Life Sciences, India: The FDA issued a warning letter to CTX Life Sciences in India after making observations of rust, insects, damaged interiors, and/or drug residues in pieces of manufacturing equipment identified as “clean”.
Investigators also found that the API were released without testing because the necessary laboratory equipment was out of order. While the company had decided to release batches “on conditional basis and as soon as UV maintenance issue rectified analysis shall be performed” the investigators could find no trace of the testing.
Our view
Last week, in our compliance round up, we had reported the shredding of documents at Hetero Labs in India. And this week, similar issues have surfaced in Italy.
It’s clear that corrupt practices of data integrity are spreading across the industry and are no longer confined to a region.
At the same time, while both European and US regulators reached a similar outcome on the compliance status of Antibioticos do Brasil, the divergent views at Granules India and FACTA Farmaceutici indicate the urgency for regulators to establish a consistent global evaluation standard for pharmaceutical manufacturing.
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