Mylan Warning Letter Exposes Challenges In Valsartan Supply Chain Chemistry
Executive Summary
Nitrosamines taint Mylan’s valsartan API solvent recovery, whether outsourced or in-house; firm mulls US FDA's request for ‘material systems review.’
A warning letter to Mylan NV is yet another indication that in response to last year’s discovery of carcinogenic nitrosamines in active pharmaceutical ingredients for certain blood pressure medications, US Food and Drug Administration investigators are turning their attention further up the pharmaceutical supply chain.
There has been a growing focus on suppliers of APIs; now the spotlight is turning to the suppliers of the API suppliers.
Nitrosamine Challenges Evolve
The Mylan warning letter, sent on 5 November and posted to the agency's website on 12 November, also shows what a difficult challenge the nitrosamine issue poses to supply chains for valsartan and other angiotensin II receptor blockers, sometimes called ARBs or sartans.
After Mylan identified recovered solvents as the source of nitrosamines in its valsartan API, the firm dropped contract solvent recyclers like Lantech Pharmaceuticals Ltd. and recycled its own solvents.
The FDA hit Lantech with a warning letter in August (Also see "US FDA Warning Letter Draws Indian Solvent Recycler Into Valsartan Crisis" - Pink Sheet, 16 Aug, 2019.) and one of its other customers, Aurobindo Pharma Ltd., in June. (Also see "Aurobindo Faulted In US FDA Warning Letter For Poor Root Cause Investigations" - Pink Sheet, 3 Jul, 2019.)
It’s all part of an uphill effort by the FDA to inspect better process chemistry into the supply chain for ARBs and other pharmaceuticals. (Also see "Enforcing A Belated Chemistry Lesson – The Nitrosamines In Sartans Saga" - Pink Sheet, 22 Aug, 2019.)
But doing its own solvent recycling hasn’t fixed the problem, probably because of contaminated tanks, so Mylan is relying on fresh solvents for now.
The Mylan warning letter called not only for better control of raw materials but also for improved cleaning validation to prevent cross-contamination in API manufacturing.
A Hunt For The Source Of Contamination
The warning letter stems from a 27 May through 5 June 2019 inspection at the Mylan Laboratories Ltd. Unit 8 plant along Highway 16 in Gaitula Chodavaram, a village in eastern India’s state of Andhra Pradesh.
Mylan’s 26 June 2019 response to the inspection’s Form 483 observations lacked enough detail or evidence of corrective actions to satisfy the FDA. The firm's 21 November 2018 investigation and a 1 January 2019 addendum had concluded the contamination came from certain recovered solvents.
But in the FDA’s view, Mylan’s conclusion that high contaminant levels in some of the solvents would not result in significant levels in its API lacked adequate scientific justification.
A field alert report Mylan sent the FDA on 13 September 2019 suggested that nitrosamine-contaminated solvent from Lantech and other solvent recovery vendors was one likely root cause of the contamination in Mylan’s rejected API batches.
How Impurities Got Into Mylan's Plant
Although Mylan did not document which solvents it stored in which tanks, the firm tried to retrospectively determine the number, identification and usage of its solvent tanks.
The warning letter noted that Mylan stopped making the API with solvents recovered by contractors, switching to in-house solvent recovery to prevent further contamination.
However, despite Mylan’s certainty that the in-house solvent recovery process would not produce any of the nitrosamine impurities, the firm detected just such an impurity at levels exceeding its specification limit according to its solvent recovery process performance qualification report.
Mylan attributed that surprising finding to its use of equipment it had previously used to store materials intended for destruction.
For the time being, Mylan told the FDA it would continue to use fresh solvents until it can validate in-house solvent recovery.
That’s fine, the FDA told Mylan, but only if the firm commits to testing solvents, whether fresh or recovered, for nitrosamines prior to release for use in API manufacturing.
Request For ‘Material System Review’ Casts Broad Net
In the warning letter, the FDA requested information about Mylan’s investigations on recovered solvents, its program for qualifying the performance of API manufacturing and solvent recovery processes, its raw materials controls, an analysis of storage tanks, related specifications and test methods, and a comprehensive, third-party review of its material system.
The information request is quite broad, applying to all APIs that Mylan manufactures and to all its material suppliers.
As part of the material system review, Mylan must report on the adequacy of its oversight of the quality of all the firm’s material suppliers. That includes the qualification standards for supplier selection and lifecycle evaluations for ensuring their continued acceptability.
Cross-Contamination Questions
The cross-contamination concerns raised by the warning letter focused on inadequate cleaning of non-dedicated equipment.
Lint-free cloths became stained with API residue after someone wiped certain chutes with them. Mylan responded by grinding and polishing the chutes, updating its cleaning procedures, reviewing investigations into complaints and out-of-specification results, and testing batches for “extraneous matter.”
But this wasn’t enough, the FDA said, because “cross-contamination cannot be assumed to be uniformly distributed and testing alone is insufficient to mitigate the observed contamination hazards.”
The warning letter went on to call for an independent assessment of cleaning effectiveness and improvements to Mylan’s cleaning validation program.
The FDA addressed the warning letter to Mylan CEO Heather Bresch with a copy to Chinnikrishna Reddy, head of API site operations at the plant.
Despite Redactions, Warning Letter Gives Away API’s Identity
The FDA redacted all mention of specific drug products, APIs, solvents and impurities from the public version of the Mylan warning letter that the agency posted online.
However, the redacted warning letter make it clear that it concerns nitrosamine contamination of valsartan because it says Mylan recalled all batches of the undisclosed API from the US market in December 2018, and the FDA’s weekly enforcement report says Mylan only had one recall event that month, which was for the recall of all US lots of valsartan-containing products within expiry due to traces of a nitrosamine impurity, N-nitrosodiethylamine, or NDEA, in the valsartan API that the firm had manufactured.
[Editor's note: The FDA 13 November revised its redaction of the Mylan warning letter's public version, removing redactions of specific drug products and APIs such as valsartan, impurities such as nitrosamines including NDEA and NDMA, impurity limits and tested levels, while leaving redactions of solvent names and adding redactions of information about an import alert and a previous warning letter that identified Lantech as one of Mylan's contract solvent recyclers. Follow this link for a copy of the revised warning letter.]