Buildings not maintained in “good state of repair”; inappropriately designed drug manufacturing equipment leading to problems in cleaning and maintenance; quality assurance department not physically checking the cleanliness of rooms and equipment prior to start of manufacturing — these were some of the observations of the US Food and Drug Administration (USFDA) after its 5-day inspection of Ankleshwar plant of Glenmark Pharmaceuticals, done in December last year.
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“Equipment used in the manufacturing of Active Pharmaceutical Ingredients (APIs) in intermediate area are not of appropriate design to facilitate operations for its cleaning and maintenance,” said the USFDA after inspecting the plant.
Elaborating on this particular topic, the USFDA stated that it observed “white residue on the walls of Reactor ID 1519 after batch to batch cleaning performed; white residue on the walls and visible dents on the bottom of Reactor ID 1524 after product change cleaning performed; white residue and brown residue which appears to be rust on the walls of Reactor ID 1502 after batch to batch cleaning performed; white residue on the walls and shaft of Reactor ID 1532 after batch to batch cleaning performed”. It added that there was brown powder, approximately 100 gram, at the bottom of one equipment, after batch to batch cleaning was performed.
On February 21, Glenmark had informed the BSE that it has received four observations for this plant from the USFDA via Form 483. A USFDA Form 483 is issued to a company’s management at the conclusion of an inspection when its investigators have observed any conditions that in their judgement may constitute violations of the Food Drug and Cosmetic (FD&C) Act and other related Acts.
The plant was inspected by the USFDA from December 12 to December 16 last year. The Indian Express reviewed the Form 483 that was issued to the company. “Buildings used in the manufacturing of API drug products are not maintained in a good state of repair,” said the third observation.
While walking through the plant, in one room of the “classified area for final stages of API product manufacturing”, the USFDA observed “chipped corners and cracked paint between ceiling and wall.” In another room, the regulator observed that “two patches on the ceiling are not evenly plastered and painted” and there was “chipped paint on the door”. In the room where the employees were packing finished API products, there were “not evenly patched dented floors”.
In response to the specific queries of The Indian Express related to these observations, the Glenmark Pharmaceuticals spokesperson said: “The API plant at Ankleshwar, India was inspected by the USFDA in December 2016. We received four observations from the FDA via the form 483. We responded to the observations in January 2017. At this point in time, we have no outstanding items with the USFDA regarding this plant. The Form 483 is an integral part of the inspection process which is used to communicate inspection observations by the USFDA after it audits the manufacturing facility.”
Many other Indian pharmaceutical companies such as Wockhardt and Dr Reddy’s Laboratories have recently received similar adverse observations from US drug regulator.
In its second main observation, the USFDA stated in Form 483: “The responsibilities and procedures applicable to the quality control unit are not fully followed.” It added that the company’s quality assurance (QA) department is “lacking (in) physical check of the rooms and equipment cleanliness prior to starting of manufacturing”. Moreover, the regulator found that “there is no procedure in place to describe the acceptance criteria by QA department of equipment and room clearance prior to all stages of API manufacturing”.
In its first main observation, the USFDA observed that the company did not perform test method validation/verification for a total of 165 test methods and 160 test methods, which are used to test and release raw materials and intermediates, respectively, during the manufacturing of APIs.
On February 21, Hyderabad-based Dr Reddy’s Laboratories had also informed the BSE that the US health regulator has made three observations after completing inspection of its Miryalaguda facility. The three observations of the USFDA were: “The specificity of test methods has not been established; procedures describing the calibration of instruments are deficiently written or followed; records maintained of any modification of an established method employed in testing do not include the reason for the modification, the data to verify that the modification produced results that are at least as accurate and reliable for the material being tested as the established method.” Dr Reddys Laboratories did not respond to the queries of The Indian Express.