Editor’s Corner—Drug approval delays due to manufacturing are a troubling trend in the industry

FDA sign
In a sign of the times, a half-dozen NDAs were delayed this year when the FDA raised questions about manufacturing.

Roche this week said the FDA pushed the PDUFA date for its fast-tracked multiple sclerosis drug Ocrevus into next year to give the FDA time to look over new info on its manufacturing process. It was the sixth drug approval delayed this year because of manufacturing matters, five of which were the subject of complete response letters.

The FDA so far this year has issued only 12 CRLs, so those five that tie back specifically to manufacturing represent more than 40% of the total. The FDA insists that is not doing anything differently in reviewing the manufacturing element of drug approvals, that it has “not conducted a more formal analysis of this issue.”

Perhaps not, but we know the FDA in recent years has made quality a mantra for drug manufacturers. It is in the process of creating a quality scorecard that will use metrics to suggest which plants may be having issues so that it can make more frequent trips to those that appear at risk. And after some criticism of past failures, the FDA is making sure that the right hand knows what the left hand is doing, so there is little chance that a manufacturing concern will slip by in the approval process.

Another aspect of the matter may be that more NDAs are for sterile injectable drugs, and they are notoriously harder to manufacture than pills. One of the CRLs issued this year was based on problems uncovered by the FDA during the inspection of a Sanofi plant in France that is responsible for the fill-finish of the experimental IL-6 inhibitor sarilumab that it is developing with Regeneron.

A Form 483 from a reinspection of that plant in July contains 13 observations, some for problems left unresolved from the earlier inspection. It points to issues with mold and bacteria contamination at the plant that the FDA says Sanofi did not thoroughly explore to sufficiently determine a root cause. It also includes sharp rebukes to the Sanofi for repeatedly refusing “requested documentation for review of the CBER regulated product.”

In many of the cases in which CRLs were sent, drugmakers expressed surprise that the FDA was not satisfied with their manufacturing process. Maybe therein lies the real problem. Perhaps too many drugmakers are sweating the other details and taking manufacturing for granted.

Mark Brian Anderson of Biotech Pharma Solutions, who works with ALKU, had these observations about that idea. His review of the matter led him to conclude the FDA is being more responsive to ensure that new drugs are safe and effective according to the regulations.

“Manufacturing details, which are under the manufacturer’s control, may not be on the top of the list as exciting review and reading, but failure to pay attention to the plethora of details will cost you money and maybe your competitive advantage in the global marketplace,” Anderson said.

Competitive advantage. That is the multiplier in this equation. There is cost when the FDA says manufacturing upgrades are called for, and time is money, so any delay has a domino effect that adds up. But as Anderson points out, what seems like a minor slip can lead to a delay and that could mean a competitor gets a leg up. Every drugmaker understands the costs of losing competitive advantage.

Of the drugs delayed by CRLs this year, in only one case was the drugmaker and its contractor able to quickly recover and get an approval within weeks. The others are still pending approval. In some previous situations, it has taken drugmakers years to resolve manufacturing issues to the FDA’s satisfaction and get a drug approved and to market. That is certainly a big window for competitors to exploit.

This is one of five significant trends you will find discussed in today’s FiercePharma that range from the impact of politics in the new year to what the wave of biosimilars might mean. Please read and give some thoughts to this ever changing industry. Thanks for your attention to our newsletters throughout the year. This is our last publication of 2016. We are taking a publishing break until Jan. 3, although we will be updating our websites throughout the holidays.

If you want the full scorecard on what we see coming up in 2017, please read these:

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Eric Palmer