Biocon, Dr Reddy’s Might Be Out Of The Woods On GMP Issue
Executive Summary
Two Indian firms – Biocon and Dr Reddy’s – have received crucial establishment inspection reports (EIRs) from the US FDA amid improved compliance levels at their manufacturing sites.
Two Indian firms seeking to set right compliance deviations at their sites appear to have made notable gains. Biocon Ltd. and Dr. Reddy's Laboratories Ltd. have received establishment inspection reports [EIRs] from the US Food and Drug Administration at their sites in Bangalore and Duvvada respectively in India.
The EIR for the Biocon’s aseptic drug product facility states that the inspection stands closed, though the FDA has classified the outcome of this inspection as VAI (voluntary action indicated), Biocon said.
A VAI inspection classification usually suggests that objectionable conditions or practices were found that do not meet the threshold of regulatory significance. Inspections classified with VAI violations are typically more technical violations of the Federal Food, Drug, and Cosmetic Act .
Industry experts maintained that while an EIR, with a VAI classification, is considered generally positive, firms need to monitor compliance issues closely to ensure no repeat deviations or unsatisfactory implementation of corrective and preventive actions (CAPAs).
“We are confident that we have implemented most of the CAPAs,” Mazumdar Shaw, Biocon
Biocon’s chair Kiran Mazumdar Shaw was reported in a television interview as saying that if the CAPAs are not carried out in a satisfactory way, the FDA can “come down on you in terms of observations and 483”. A Form 483 is a notice of the US FDA's inspectional observations that lists deficiencies in the quality system.
“We are confident that we have implemented most of the CAPAs,” Mazumdar Shaw added in the interview.
Regulatory Transparency
In the case of Dr Reddy’s Duvvada unit in Visakhapatnam, the company said that the FDA had explained that it had released the EIR in order to be “transparent about its regulatory process” but that the inspection had not been closed and the site’s status “remains unchanged”.
The FDA rider is perhaps significant given that EIRs are generally provided when no enforcement action is contemplated, or after enforcement action is concluded. An EIR typically includes, among others, the investigator’s narrative report and any refusals, voluntary corrections, or promises made by the firm’s management.
“We are planning to request a re-inspection in 2018 after further discussion on scheduling with the FDA,” Dr Reddy’s said in a filing with the Bombay Stock Exchange on Nov 21.
Nimish Mehta, founder of Research Delta Advisors, told the Pink Sheet that the FDA was, in general, becoming more “transparent and communicative” when it comes to the good manufacturing practice (GMP) status of sites.
Mehta noted that the US Generic Drug User Fee Amendments (GDUFA) II refers to how by Oct. 1, 2018, the FDA expects to communicate to the facility owner final inspection classifications that do not negatively impact approvability of any pending application within 90 days of the end of the inspection. As per the GDUFA II commitment letter, the FDA has also agreed, among other aspects, to ongoing periodic engagement with industry stakeholders to provide updates on agency activities and seek stakeholder feedback.
“The Dr Reddy’s EIR perhaps suggests that it is unlikely that there will be any further escalation in issues at Duvvada. But the ball is clearly in the company’s court,” Mehta said.
The Duvvada unit had earlier failed to make the cut in an audit by the German regulator. (Also see "Another Dr Reddy’s Plant Runs Afoul Of German Regulator" - Pink Sheet, 11 Sep, 2017.)
Biocon’s EIR
The stakes appear rather high for Biocon, given that the Bangalore site caters to firm’s biosimilars pipeline.
The EIR comes just weeks before the extended Dec. 3 FDA target action date for Biocon and partner Mylan NV’s biosimilar trastuzumab 351(k) application. The extension of the target action date from Sept. 3 was essentially to review “some of the clarificatory information submitted” to the agency as part of the application review process, Biocon had indicated in August.
“This three-month extension has no impact on the anticipated timetable for commercialization of this product in the US,” the Bengaluru-based firm maintained at the time.
A Biocon statement said that the latest EIR pertained to the cGMP (current GMP) inspection of its aseptic drug product facility that was audited between May 25 and June 3. The company declined to comment any further, including whether the FDA’s previous concerns on inadequate data – seen as a prickly area by some analysts in terms of inspectional outcomes – have been successfully addressed.
The FDA inspection at Biocon’s Bommasandra, Bangalore, site conducted between May 25 and June 3 had earlier listed several deviations including deficiencies in the aseptic processing area and inadequate laboratory controls. The agency had, at the time, also noted that laboratory records at the Bangalore unit did not include complete data derived from all tests, examinations and assay necessary to assure compliance with established specifications and standards.
Biocon did not clarify whether the drug substance facility at the Bangalore site would need separate FDA clearances. A pre-approval inspection by the FDA between March 27 and April 7 this year pertaining to the firm’s drug substance and drug product manufacturing unit there had flagged up compliance deviations. (Also see "FDA Inspection Yields Insight Into Biocon/Mylan Biosimilars Manufacturing Challenges" - Pink Sheet, 11 Jul, 2017.)
Rub-Off On EMA Inspection Outlook?
It’s also unclear if the developments on the compliance front with the FDA could improve the outlook for inspections by the European Medicines Agency for the two firms. This is especially so in the general backdrop of the coming into operation of the mutual recognition agreement between the EU and the US to recognize inspections of manufacturing sites for human medicines conducted in their respective territories. (Also see "US/EU Agreement Will Reduce Global Import Testing Burden" - Pink Sheet, 2 Nov, 2017.)
Biocon and Mylan had earlier retracted applications for their biosimilar versions of trastuzumab and pegfilgrastim in the EU in the backdrop of manufacturing compliance lapses. (Also see "More Questions As Biocon Pulls EU Filings For Two Biosimilars" - Pink Sheet, 16 Aug, 2017.) A pre-approval inspection by the French regulator, ANSM, had earlier flagged compliance deficiencies at Biocon’s Bommasandra site for three biosimilars – pegfilgrastim, trastuzumab and insulin glargine and the Indian firm had, at the time, indicated that it would require a re-inspection of the “drug product” facility.
Earlier this month, Mylan resubmitted the marketing authorization applications for biosimilar trastuzumab and pegfilgrastim with the EMA. Biocon, at the time, said that it had completed the CAPAs, including the facility modifications, in response to the audit observations and expects these to be verified during re-inspection.