Regulatory Focus™ > News Articles > Warning Letter Resurrects Issue of Makena and FDA's Use of Enforcement Discretion

Warning Letter Resurrects Issue of Makena and FDA's Use of Enforcement Discretion

Posted 13 March 2014 | By Alexander Gaffney, RAC

A Warning Letter sent by the US Food and Drug Administration (FDA) this week offers yet another addition in the long and interesting chapter of KV Pharmaceuticals' Makena (17-hydroxyprogesterone  caproate).


In 2011, FDA approved Makena under an orphan drug designation. While the drug had been used by doctors for years to prevent premature births, KV was the first company to bring Makena through clinical testing. Under the terms of FDA's approval, all other manufacturers would have to take the drug off the market for at least seven years.

Shortly after approval, KV made headlines by announcing that the price of the drug would increase dramatically from less than $100 per dose to as much as $1,500 per dose, making the full cost of treatment as high as $30,000 for some. The company later relented and brought the cost down to $690 per dose, but the damage had already been done to the company's public image.

Shortly after approval, FDA announced that it would continue to allow small-scale compounding pharmacies to make the drug.

"In order to support access to this important drug, at this time and under this unique situation, FDA does not intend to take enforcement action against pharmacies that compound hydroxyprogesterone caproate based on a valid prescription for an individually identified patient unless the compounded products are unsafe, of substandard quality, or are not being compounded in accordance with appropriate standards for compounding sterile products," FDA wrote.

Shortly thereafter, KV submitted samples to FDA in an attempt to cast doubts about the safety and quality of compounded versions of Makena. However, FDA ultimately dismissed these claims, saying that it had not found sufficient evidence to cast doubt on the practice of compounding Makena.

FDA's analysis "did not identify any major safety problems," it wrote, though it noted that FDA-approved drugs like Makena do offer "a greater assurance of safety and effectiveness." As such, FDA's policy of enforcement discretion with respect to Makena was maintained.

KV would later sue FDA, arguing the agency's use of enforcement discretion was unlawful and had caused its bankruptcy. FDA argued that the challenge was without merit, and ultimately prevailed in September 2012.

Enter: A Compounding Crisis

The very next month, a compounding pharmacy in Massachusetts put pharmaceutical compounding at the top of FDA's regulatory agenda and legislators' political agenda. Products compounded by the New England Compounding Pharmacy (NECC) were linked to a massive outbreak of fungal meningitis, which left hundreds ill and more than 60 dead.

FDA was spurred into action, and ultimately initiated a massive crackdown against compounding pharmacies, sending dozens of Warning Letters, recall notices and Form 483s (notices of deficient findings) to compounders around the country.

Among those letters were several sent to companies that compounded hydroxyprogesterone caproate-a compounded version of Makena.

Portage Pharmacy (February 2014), for example, was found to have inadequately verified the effectiveness of methods used to sterilize its compounded version of hydroxyprogesterone caproateduring a February 2014 inspection. That same pharmacy had also failed an earlier FDA inspection, again regarding sterilization of hydroxyprogesterone caproate.

Another compounding pharmacy, RX3 Pharmacy (February 2014), was also put on notice by FDA for allegedly failing to properly sterilize equipment used to make hydroxyprogesterone caproate. An inspection of Stewart Compounding Pharmacy in March 2013 found similar deficiencies.

Warning Letter and Makena

But since the start of FDA's crackdown, no Warning Letters have been sent to any compounder of Makena.

This week, that changed.

In a 28 February 2014 Warning Letter to Village Fertility Pharmacy, FDA alleged that the compounding pharmacy had been producing hyroxyprogesterone caproate under "insanitary conditions," putting the company's patients at risk. The letter followed a 2013 Form 483 alleging similar deficiencies.

The company reportedly used non-pharmaceutical grade sterilization equipment, and did not monitor the gloves worn by its employees for microbial contamination. The company also failed to do routine airborne particle testing in its ISO 5 cleanroom environment-a required step for any manufacturer of sterile products.

FDA noted that the above steps contributed to an environment that could not be confirmed to be sufficiently sterile--a problem that became evidently clear when FDA came across products with "dark visible and white/translucent particulates."

"FDA laboratory analysis confirmed the presence of foreign and particulate matter in vials of several drug products produced by your firm and collected during the inspection - Hydroxyprogesterone Caproate Injectable, Progesterone in Ethyl Oleate Injectable, and Progesterone in Sesame Oil Injectable," FDA wrote in its Warning Letter.

The company has reportedly initiated a recall of all stock of hydroxyprogesterone caproate, though FDA did not have any record of the recall on its website, and neither did the website of Village Fertility Pharmacy. News of the recall was, however, found on the website of a local Fox News affiliate in Boston.

However, given FDA's ongoing troubles with compounding pharmacies-and Makena in particular-it may be time for the regulator to revisit its enforcement discretion policy.


Warning Letter to Village Fertility Pharmacy

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