Cadila Shifts US Injectables Production From Plant After Tough FDA Inspection
Executive Summary
Expert investigators found many problems at Ahmedabad plant, warning letter and Form 483 report show.
Five months after a visit from a US inspection team that included sterile drugs expert Thomas Arista, Cadila Healthcare Ltd. informed the US Food and Drug Administration it would no longer produce injectable drug products for the US market at the facility in Village-Moraiya near Ahmedabad in western India’s Gujurat State.
The FDA noted Cadila’s plan to “permanently cease” such production in a warning letter it sent the firm on 29 October and published 12 November. The warning letter cautions Cadila to notify the agency in writing “if you decide to revisit your decision and resume manufacturing injectable drugs for the US in the future.”
The two-week inspection was a bit of a nightmare for Cadila, judging from the warning letter and the 23-page, 14-observation Form 483 report the firm received at the inspection’s 3 May 2019 conclusion from Arista, Justin Boyd of the FDA’s national drug cadre, and Rita Kabaso of the agency’s office of International Programs.
Take, for example, the matter of the closed-circuit television system Cadila installed for parenteral fill lines in 2015 to, as change control documents cited in the Form 483 report said, “keep close watch on production practices and upgrade the facility.”
The investigators found out Cadila never used the system to record production operations or aseptic media fills. Instead the firm relied on a small camera on a tripod in a personnel corridor to record media fills through a small window that gave a partially obstructed view of the fill lines. (Also see "The Quality Lowdown: Quality Vision Falls Short At Various US and Indian Facilities" - Pink Sheet, 10 Jun, 2019.)
The warning letter did not mention the CCTV system, focusing instead on four main areas of concern stemming from the inspection, which ran from 22 April through 3 May. The facility was cited for cross-contamination, sterilization failures, poor aseptic practices and lax environmental, and personnel monitoring.
Tablet Cross-Contamination
Cleaning procedures were inadequate for non-dedicated equipment used in the production of solid oral dosage forms of potent and non-potent compounds, the FDA said.
The agency’s investigators saw residues from different products on equipment marked as clean.
Cadila later confirmed the presence of multiple active ingredients on product-contact surfaces and in reserve samples from multiple batches.
The warning letter noted that Cadila subsequently recalled numerous batches manufactured in a part of its facility that is dedicated to potent compounds.
On 6 May, Zydus Pharmaceuticals (USA) Inc., a related company based in Pennington, NJ, recalled more than 109 million tablets of anastrozole, pramipexole dihydrochloride and methylprednisolone that Cadila had manufactured at the plant. Anastrozole reduces estrogen levels to treat breast cancer in postmenopausal women; pramipexole dihydrochloride is a dopamine agonist used to treat Parkinson’s disease; and methylprednisolone is an adrenocortical steroid that treats a wide range of diseases by reducing immune response and inflammation.
However, when Cadila reviewed the incident, the firm concluded that the cross-contamination did not pose any risk to patients, based on what the FDA deemed an unwarranted assumption that carryover residue of active ingredients would be uniformly distributed.
The warning letter went on to prescribe a robust approach to assessing, correcting and preventing the cross-contamination issue.
Autoclave Failures
The warning letter’s second area of concern was around periodic requalification of moist heat sterilization equipment, or autoclaves, which failed multiple times when sensors indicated that the requisite temperature had not been reached.
Additionally, after an incubation period following an attempted requalification in March 2019, multiple biological indicators that should have been sterilized showed microbiological growth.
The warning letter said this led to a recall. It could be the recall that the FDA’s enforcement reports say Sagent Pharmaceuticals, Schaumburg, IL, initiated on 30 April for ketorolac tromethamine injection, USP, due to “microbial growth detected during a routine simulation of the manufacturing process” at an undisclosed contract manufacturer.
Poor Aseptic Practices
Arista and his colleagues saw workers leaning over sterilized stoppers and doing other things during aseptic setup and filling operations that may have compromised sterility.
They also observed deficiencies in cleanroom design that created turbulence in what should have been laminar air flow, and they saw that smoke studies failed to simulate multiple critical interventions.
The Form 483 report describes irregularities in aseptic process validation such as the removal of media filled vials that were exposed during fill room operators’ manual interventions.
Records showed 1,328 media filled vials were culled during a 16 January 2019 simulation, and similar number of vials during other media fill simulations listed in the 483 report.
The 483 report provided additional detail regarding issues with smoke studies as well as air pressure differentials.
Environmental, Personnel Monitoring
There were also concerns about environmental and personnel monitoring, including a failure to trend and assess growth on samples taken from personnel in aseptic processing areas.
The warning letter referred Cadila to the FDA’s September 2004 guidance on current good manufacturing practices for sterile drug products produced by aseptic processing.
Executive Oversight Questioned
The warning letter noted that Cadila had promised to remedy similar cGMP violations cited in previous warning letters in June 2011 and December 2015, but did not, a sign the FDA said of inadequate executive management oversight and control.
Editor’s note: This article was updated 15 November with corrections to the headline and first paragraph to reflect the fact that Cadila will continue to produce injectable drug products for the US market, just not at the facility near Ahmedabad.