The Quality Lowdown: Pandemic Inspection Results Trickle In As Investigators Venture Out

US FDA inspections lead to warning letters for Aurobindo and Health Plus, while Emergent BioSolutions site escapes nearly unscathed; Sun waits for Halol revisit and Jubilant suffers poor-quality costs as agency investigators resume domestic surveillance post-omicron.

 

As US Food and Drug Administration investigators venture out more, there will be new opportunities for drug manufacturers to show off the quality systems that have been carrying them through the pandemic relatively unobserved.

With the wave of omicron variant COVID-19 infections declining steeply in the US, the FDA this week resumed domestic surveillance inspections, paused since December. They won’t be unannounced like in the pre-COVID days, but they will be happening.

The agency is continuing to conduct foreign surveillance inspections when cleared by the host country and countenanced by the US Centers for Disease Control and Prevention, and mission-critical inspections have been continuing in the US and abroad regardless of COVID-19 conditions to the extent possible.

Meanwhile, warning letters and inspection reports continue to filter out from the agency and the regulated community with new insights on pandemic and in cases pre-pandemic inspection findings.

Deviations Devolve Into Warning Letter For Aurobindo

Efforts at Aurobindo Pharma Limited's Unit I in Borpatla, India, to allow more impurities in a starting material for an active pharmaceutical ingredient and to resolve critical deviations in the transfer of a gas chromatography-mass spectrometry method triggered a warning letter from the US FDA on 12 January.

The warning letter stemmed from a 2-12 August 2021 inspection of the API plant near Hyderabad.

Aurobindo increased a limit for the starting material after rejecting several lots that exceeded the specification. To justify the increase, Aurobindo conducted a laboratory-scale study that didn’t consider the full range of possible impurities. There were also problems with a purging step used in the study and questions about the related substances analytical method used.

The Quality Lowdown

The Lowdown is a recurring Pink Sheet column offering quick takes on manufacturing quality and compliance policy.

The company’s investigation into split peaks observed during GC-MS method transfer was inadequate because it failed to consider all potential equipment sources, the FDA said. Aurobindo blamed the discrepancy on a dirty or degraded column, and the problem went away when the company replaced the column. But the FDA still had questions.

The warning letter left Aurobindo with some assignments, including a review of its system for investigating deviations and a review of all invalidated out-of-specification results for US-bound batches.

The agency noted that it had cited similar deviations during a July 2019 regulatory meeting that the company had promised to fix.

Health Plus Laxatives Fail FDA’s Smell Test

A 29 December 2021 warning letter points out some good manufacturing practices that have been missing for a decade at Health Plus Inc., Chino, CA, still were missing during a 23 June to 1 July 2021 inspection.

The company redistributed returned drug products without properly inspecting and testing them, relying instead on organoleptic examination methods like sniffing.

Health Plus also would combine returned capsules into new lots and give them new three-year shelf lives unsupported by stability data.

The company did not validate the manufacturing process for an over-the-counter laxative that it reformulated in December 2017 until a year later, but even then, the validation protocol was based on data from the previous formulation.

The company also failed to adequately validate its assay method for releasing the laxative, the FDA said.

There has been no stability testing since before the reformulation, so there is no basis for the laxative’s expiration date.

The company replied, the warning letter said, that the stability study was delayed “because of restrained resources for the quality unit.”

The warning letter reminded the company that the FDA had pointed out the inadequacy its stability programs during inspections in 2013, 2015, 2018 and 2021.

The FDA observed that the company’s quality unit had failed to establish procedures that it had promised after inspections in 2012, 2013 and 2018, concluding that “we have no assurance that your corrective actions will be implemented.”

If Health Plus fails to address the shortcomings, the warning letter says there could be seizures and injunctions, and other agencies might not award contracts.

Aside From Boot Issue, Sterility Assurance Improved At Emergent Site

A September 2019 FDA inspection of Emergent BioSolutions, Inc.’s facility in Winnipeg, Canada, showed the company had made progress on sterility assurance, though it found one area for further improvement, according to the redacted establishment inspection report and Form 483 report that the agency’s Center for Drug Evaluation and Research recently posted in its electronic reading room.

The inspection conducted in support of a drug product Emergent was going to manufacture for a client included confirmation of voluntary corrections to certain observations from inspections in 2015 and 2017.

FDA found Emergent had corrected deficiencies in air handling systems for aseptic processing areas and in trend analysis recommendations that the agency had identified during the 2017 inspection.

Also corrected: observations from the 2015 inspection of missing sterilization validation procedures and deficient cleaning and sterilization procedures for aseptic processing areas.

Corrections included changes to the high efficiency particulate air filtration system for areas of a filling room that required the cleanest air.

Training improved plant personnel’s aseptic technique, FDA found.

However, Emergent needed to work on gowning, the agency said, after an investigator reported seeing a worker “grasp the outside of his sterile boot covers to unfold the vinyl boot soles” despite procedures requiring workers to unfold by grasping the inside of the boot.

The firm retrained three workers and said it would post gowning instructions on laminated placards in the gowning area.

Cloud Hanging Over Halol Plant Dims Sun’s Prospects

Credit Suisse Research said in a 3 February analyst note that it is neutral on Sun Pharmaceutical Industries Ltd. in part due to slow US generics approvals exacerbated by delayed resolution of the US FDA’s December 2019 official action indicated classification of Sun’s Halol facility in India. (Also see "Sun Site Stares At FDA Action But Dent May Be Limited" - Scrip, 30 Mar, 2020.)

The FDA will not approve drug products manufactured at an OAI-classified facility. The agency will not reclassify such facilities until it re-inspects them. Such re-inspections have not always been the highest priority for the agency during the pandemic, and the FDA has been reluctant to reclassify such facilities based on remote interactive evaluations.

Sun’s economic prospects have long hinged on expectations around the Halol plant’s quality. Fearing the worst, investors dumped its stock in September 2014 when word got out that a five-person FDA inspection team had entered the plant. (Also see "Sun Eclipsed By Fears Of U.S. FDA Probe At Halol Site" - Scrip, 11 Sep, 2014.)

The Cost Of Jubilant’s Quality Issues

Poor quality is costing Jubilant Pharmova Ltd., according to its 4 February interim report for the quarter than ended 31 December.

The Noida, India, drug maker’s interim report said that its generics business “was affected by lower volumes due to import alert at Roorkee plant, latest sartan impurities issue and pricing pressure in the US generics market.”

The Roorkee import alert stemmed from a March 2021 inspection during which FDA encountered a bottle of tablets that contained a pen cap and was not expected to have much of a financial impact. (Also see "FDA Details Observations At Stricken Jubilant Roorkee Facility" - Generics Bulletin, 6 Sep, 2021.)

Additionally, the company, formerly Jubilant Life Sciences Ltd., said an unplanned plant shutdown during the quarter reduced its active pharmaceutical ingredient business.

Recent Recalls Of Note

AuroMedics Pharma LLC, East Windsor, NJ, 26 January said it recalled one lot of polymyxin B for injection to the consumer level after receiving a complaint of hair in a vial.

Blaine Labs Co., Santa Fe Springs, CA, 27 January recalled one lot of RevitaDerm Wound Care Gel to the consumer level because one bottle of the gel was contaminated with Bacillus cereus.

Taro Pharmaceuticals North America Inc. on 27 December recalled one lot of clobetasol propionate ointment USP from the US market after routine testing by the company showed the lot was contaminated by Ralstonia pickettii bacteria.

Padagis LLC, Allegan, MI, 27 December recalled three lots of nitroglycerin lingual spray to the consumer level after receiving a complaint that a unit may not dispense, raising concern that the 12-gram spray bottles could malfunction. Sedgwick Claims Management Services is handling the recall.

Teligent, Inc., Buena, NJ, 7 December recalled two lots of lidocaine hydrochloride topical solution USP after finding that super potent stability samples after nine months in one lot and 18 months in another. Untreated local anesthetic systemic toxicity could lead to severe morbidity or death, the company said.

Edge Pharma LLC, Colchester, VT, 4 December recalled all lots of all drugs it compounded due to lack of sterility assurance, including purportedly sterile and non-sterile drugs in a variety of dosage forms and types of packaging.

Gilead Sciences, Inc., Foster City, CA, on 3 December recalled two lots of Veklury (remdesivir 100 mg for injection) after receiving a customer complaint of glass particulates, which the company investigated and confirmed.

Sandoz Inc. 1 December recalled one lot of enoxaparin sodium injection USP single-dose syringes due to a temperature excursion. A portion of the lot experienced high temperatures during shipping in September and October.