FDA finds no major safety issues for compounded 17P

• 16 samples passed USP tests for potency, purity in Makena NDA

• Four impurities identified do not raise safety concerns

Analysis by the United States Food and Drug Administration (FDA) of compounded 17α-hydroxyprogesterone caproate (17P) shows the samples meet the potency and total purity standards for Makena, the branded version of the drug.  Testing was done on 16 samples of bulk 17P active pharmaceutical ingredients (API) in response to questions from K-V Pharmaceuticals, Makena’s sponsor, about potency and purity of the compounded product.

Using methods specified by the United States Pharmacopeia (USP) and those in the Makena New Drug Application (NDA), FDA tested the 16 samples collected from compounding pharmacies, doctors’ offices, API distributors, and APIs offered for importation. All of them passed USP tests for potency and purity and met the standard for potency used in the Makena NDA. However, FDA identified 4 impurities that appeared at levels above those permitted in Makena’s NDA. The Agency was quick to add that the impurities did not raise any safety concerns.

FDA also tested 13 samples of compounded 17P prepared by 8 pharmacies, 1 of which was subpotent at 80% potency (acceptable range 90% to 110%). All of the samples met Makena’s standard for total purity, but 2 of the samples failed to meet the branded product’s standard for unidentified impurities.

Some of the same samples that K-V tested and used as the basis for their report of the problem to the FDA also were analyzed by the Agency. Three  of 26 of those samples failed to meet the standard for potency used in the Makena NDA; all hovered around 115%. However, they were not large enough for testing with the USP method. Seven of the 26 failed Makena’s standard for unidentified impurities.

The limited review unearthed no major safety concerns, but FDA noted that products approved by the Agency “provide a greater assurance of safety and effectiveness than do compounded products.” This is because in reviewing a product for approval, FDA reviews such factors as the API source used by the manufacturer, proposed manufacturing processes, and adherence to good manufacturing practices. Compounded drugs are not FDA-approved and, thus, potentially circumvent important public health requirements involving safety and effectiveness.

FDA emphasized that its normal enforcement policies for compounded drugs apply to compounded 17P.

Comment by Editorial Board Member Haywood L. Brown, MD
Preterm birth is one of the leading public health dilemmas in modern obstetrics.  A decade ago, our specialty was exhilarated by results of a randomized trial that suggested efficacy for compounded 17-hydroxyprogesterone (17-OHP) in prevention of preterm birth in women with a prior spontaneous preterm birth. In February 2011, FDA approved 17-hydroxyprogesterone caproate (Makena®) for prevention of preterm birth. That announcement was followed by controversy related to the cost of the branded drug and communications from the manufacturer suggesting that compounding pharmacies needed to stop compounding 17-OHP and that the latter product might have impurities and potency issues rendering them less safe and effective than the FDA-approved product. The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine responded with a joint statement on the relative merits of compounded 17-OHP versus Makena.  Now, FDA has answered the charge: Samples of compounded 17-OHP raise no safety concerns and meet the potency and total purity standards for the FDA-branded drug Makena®.  Of course, the real question is who is the properly selected candidate for progesterone for prevention of preterm birth, irrespective of dosing, potency, or route of administration? That answer is yet to be determined because of the elusive and complex epidemiology of idiopathic preterm birth.  

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