On May 27, 2016, AstraZeneca announced they received a Complete Response Letter (CRL) from the FDA for their sodium zirconium cyclosilicate (ZS-9) New Drug Application (NDA) (reference link). This hyperkalemia drug was developed by ZS Pharma and was generally expected to receive FDA approval when AstraZeneca acquired the company for $2.7 billion last year.

Instead of being rejected due to safety or efficacy concerns, the CRL surprisingly refers to findings from a pre-approval manufacturing inspection (PAI). Once AstraZeneca addresses these PAI concerns, the CRL requires that their resubmission undergo a new 6-month review cycle, indicating likely delays of at least a year before this drug could come to market.

Approval of AstraZeneca’s ZS-9 would have introduced a key rival drug to compete with Relypsa’s current monopoly on the hyperkalemia market, estimated to be worth $6 billion. This CRL, which appears to be solely based on manufacturing concerns, was a major blow to the company and to hyperkalemia patients dealing with an unmet need in treatment options.

What is a pre-approval inspection?

Pre-approval inspections (PAIs) are one of the stages in the drug approval process. The inspection goal is to ensure the manufacture, processing, packing, and testing of the drug are sufficient for maintaining drug quality. These inspections typically involve a systematic review of the application and the entire manufacturing process.

A PAI may be conducted at any facility listed in Module 3 of the NDA, including active pharmaceutical ingredient manufacturers, control testing labs, and packaging facilities. During a PAI, the FDA inspectors try to ensure the following at each site:

• cGMP compliance
• conformance to application
• manufacturing reliability
• authenticity and accuracy of data
• ability to scale-up
• adequacy of analytical methods

If significant issues are discovered in any of the above areas, the FDA may reject an application, regardless of the potential clinical benefit of the drug.

Why was the Astra-Zeneca CRL issued?

A PAI deficiency would likely have resulted in an “approvable” letter issued by the FDA, which simply stops the FDA review clock until the issue is resolved. While this FDA action is typically a setback because the drug approval will be delayed, it is certainly a preferable option to the NDA having to re-enter the review cycle.

The FDA no longer issues approvable letters. Instead, it has simplified its actions by issuing a CRL for any drug not approvable in its current form. These CRLs may be issued for any clinical concerns found during review or, as in the case of AstraZeneca, for any manufacturing issues found during inspection. CRLs for NDAs are classified as either Class 1 or Class 2 resubmissions, which translate into new 2-month or 6-month review cycles, respectively.

In an analysis of 61 CRLs issued from 2008 to 2013, the British Medical Journal found that the most common reasons for CRLs cited safety (n = 42, 69%), chemistry, manufacturing, and controls (n = 42, 69%), and efficacy (n = 41, 67%) (reference link). Only 13% (n = 8) of letters mentioned neither safety nor efficacy, indicating the relative rarity of CRLs issued solely for failures in PAIs.

How can you prevent this from happening to you?

Premier Consulting has guided more than 200 NDA and ANDA approvals and is the leader in 505(b)(2) submissions worldwide. We help ensure PAI readiness through PAI planning, conducting PAI readiness audits, and on-site mock PAIs. These consultations will cover everything from site cGMP compliance to the adequacy of material handling systems, manufacturing and packaging processes and analytical methods and ensures that the site is ready for the inspection. Premier Consulting can work with you to ensure that late-stage inspection issues do not delay your drug approval. Contact us here.