U.S. FDA Flags Operational, Procedural Lapses At Cipla’s Goa Unit

The U.S. FDA inspected Cipla’s formulation-making facility in Goa from Aug. 16-26.

<div class="paragraphs"><p>Source: Unsplash</p></div>
Source: Unsplash

The U.S. drug regulator has flagged six operational and procedural lapses at Cipla Ltd.’s Goa facility.

The U.S. Food and Drug Administration inspected Cipla’s formulation manufacturing facility in Goa from Aug. 16-26, the company had said in its Aug. 26 exchange filing. “On conclusion of the inspection, the company has received six observations with some referencing to the observations made during the September 2019 inspection. There are no data integrity observations.”

A Form 483 is issued when investigators have observed any condition that in their judgment may constitute violation of the Food Drug and Cosmetic Act and related acts.

The company, the filing said, would work closely with the U.S.FDA and was committed to address these within the stipulated time. The drugmaker had disclosed that the manufacturing facility was previously inspected in September 2019 and a warning letter was received in February 2020.

Nomura has obtained a copy of the recent observations from the FDA. Three of these six observations are a repeat and indicate operational deficiencies. Also, these three observations were the ones that had led to the “warning letter” at the site in February 2020, it said in its Sept. 19 report.

Operational Deficiencies—Repeat Observations

  • The environmental monitoring of the aseptic filling area is not adequate. During August 2018-January 2019, there were cases of environment excursions (higher than the accepted level of microorganism or particulate) noticed that led to Cipla rejecting several production batches. The investigation led to the conclusion that the excursions were on account of sampling errors. However, adequate actions were not taken to prevent such sampling errors, as per the Form 483 observation. The company made changes to the environment monitoring protocol that led to discontinuation of monitoring in some places or reducing threshold (Grade C rather than more stringent Grade A requirements). Cipla released batches to the U.S. market despite presence of microbial growth as they met the Grade C requirements (but not Grade A).

  • Smoke studies to evaluate air flow pattern is either not performed or are inadequate. Smoke studies help to establish proper air flow that ensures contamination is prevented in aseptic manufacturing area.

  • Deficiencies are observed during cleaning of equipment by operators. This has the potential to lead to contamination. The cleaning procedure details are not comprehensive enough. Further, the inspection noted that a disinfection procedure was not qualified to establish effectiveness.

Procedural Lapses

  • The control on computer is not adequate as it allows room for making changes. Critical machine parameters that are established during qualification process are not documented. The lab data can be changed before it is saved. There is no audit trail of changes made before the data is saved.

  • The procedure for reviewing electronic data for audit is generic in nature. The specific requirements of a software are not elaborated in the procedure. Also, the procedure for audit does not elaborate the requirements on how many sequence/data are to be reviewed.

  • Procedure for cleaning, maintenance and sanitising schedule for equipment is deficient.

Goa, the brokerage said, accounted for about $60 million (Rs 475 crore) in sales. This included products such as gPulmicort (asthma), Cipla’s second-largest product in the market currently. “We, however, think sales contribution from the Goa site has reduced since, due to price erosion in the base portfolio and site transfer of products like gPulmicort to Indore. The company has also suspended operations of some sterile lines at the site following the September 2019 inspection.”

Cipla has not shared the number of pending ANDAs from the site, said Nomura. But the management mentioned that gAbraxane (breast cancer) was one key filing from the site. The company might be making site transfer efforts due to uncertainty on timeline for clearance of the Goa site. Given the outcome of the recent inspection, which included three repeat observations and high sensitivity around contamination in sterile products, the site may remain classified under “official action initiated”.

The drugmaker has yet to respond to BQ Prime’s emailed queries on the implications of the observations and their impact on future approvals and launches. It’s also yet to comment on the steps being taken to address these issues and the expected timelines.

Since Aug. 26, shares of Cipla have gained 4.5% compared with a 1.4% rise in the benchmark Nifty 50.