FDA document lays out issues undermining approval of AstraZeneca's ZS Pharma drug

The FDA has posted a Form 483 that was the basis of a second complete response letter issued to AstraZeneca over its new hyperkalemia drug. (AstraZeneca/Herzog & DeMeuron)(AstraZeneca / Herzog & DeMeuron)

The FDA has twice rejected AstraZeneca’s application for a new drug to treat hyperkalemia because of manufacturing concerns. The reasons why became clearer Wednesday when the agency posted a document outlining the issues that have regulators furrowing their brows.

The highly redacted FDA Form 483 was issued (PDF) to AstraZeneca’s ZS Pharma unit following a January inspection of its plant in Coppell, Texas. That's where it is manufacturing ZS-9, a potential blockbuster treatment that was the target in AstraZeneca’s $2.7 billion buyout of ZS Pharma in 2015.

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The 11-page citation includes five observations over concerns ranging from incomplete validation records to particulates in some samples. There were missing audit trails for some equipment and problems with scale-up, with five out-of-spec reports issued in four months, all illustrating the difficulty that ZS Pharma is having getting the API to meet its criteria.

The ongoing problems led the FDA in March to issue a second complete response letter to AstraZeneca for the drug, after having rejected it in May 2016 over manufacturing difficulties.

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The U.K. company insisted it is getting to the root of its problems. When the CRL was issued in March, the drugmaker said, "The manufacturing process for ZS-9 is novel and complex, and since the feedback from the May 2016 CRL AstraZeneca has addressed most of the 12 observations and open items from the FDA, including operational manufacturing practices, quality processes and systems."

AZ and ZS Pharma are committed to working with the FDA to resolve the remaining matters as soon as possible, the drugmaker said.