Updated FDA Statement on Compounded Versions of hydroxyprogesterone caproate (the active ingredient in Makena)

For Immediate Release: June 15, 2012
Media Inquiries: Erica Jefferson, 301-796-4988, Erica.Jefferson@fda.hhs.gov

Updated FDA Statement on Compounded Versions of hydroxyprogesterone caproate (the active ingredient in Makena)

FDA (or the Agency) approved Makena (hydroxyprogesterone caproate) in February 2011 for the reduction of the risk of certain preterm births in women who have had at least one prior preterm birth. Beginning many years before Makena was approved, a version of the active ingredient of Makena has been available to patients whose physicians requested the drug from a pharmacist who compounded the drug.

As explained in a November 8, 2011 statement, in October 2011, FDA received information from Makena’s sponsor, K-V Pharmaceuticals, regarding the potency and purity of samples of bulk hydroxyprogesterone caproate active pharmaceutical ingredients (APIs) and compounded hydroxyprogesterone caproate products. The Agency explained that FDA had carefully reviewed the data K-V submitted and would conduct an on-site review of the laboratory analyses. The Agency also stated that FDA had begun its own sampling and analysis of compounded hydroxyprogesterone caproate products and the bulk APIs used to make them.

FDA has completed its review, and the Agency is now providing a brief summary of the results. FDA collected samples of compounded hydroxyprogesterone caproate products and hydroxyprogesterone caproate APIs. These samples generally were collected from compounding pharmacies, doctor’s offices, API distributors, and APIs offered for importation.

• FDA tested 16 samples of hydroxyprogesterone caproate API using the methods specified in the United States Pharmacopeia (USP) as well as the methods used in the Makena new drug application (NDA). 
  • All 16 API samples passed USP tests for potency (97-103 percent) and purity and all 16 API samples passed the potency tests in the Makena NDA.
  • All 16 of the API samples passed the total purity standard in the Makena NDA but failed the Makena NDA’s limit for unidentified impurities.
  • FDA also isolated and identified four impurities that appeared at levels above those permitted in the Makena NDA. Based on information available to FDA, the impurities observed in these samples do not raise safety concerns.  
• FDA also tested 13 samples of compounded hydroxyprogesterone caproate prepared by eight pharmacies.
  • One of 13 samples was subpotent and was in the range of 80 percent of declared potency. (The standard for potency is 90-110 percent). All 13 of the samples met the standard in the Makena NDA for total purity.
  • Two of the 13 samples failed to meet the standard for unidentified impurities in the Makena NDA.

FDA also obtained the available retained samples of compounded products from the laboratories that K-V hired to perform the tests on the compounded products that were submitted to the agency in October 2011. FDA’s testing of the retained samples found that three of 26 samples failed the standard for potency (90-110 percent) using the method in the Makena NDA. (The samples were not large enough for FDA also to test them using the USP method.)  The three products that failed potency testing were in the 115 percent range. Seven of 26 samples failed the standard for unidentified impurities in the Makena NDA.

Although the analysis of this limited sample of compounded hydroxyprogesterone caproate products and APIs did not identify any major safety problems, approved drug products, such as Makena, provide a greater assurance of safety and effectiveness than do compounded products. Before approving the Makena NDA, FDA reviewed manufacturing information, such as the source of the API used by its manufacturer, proposed manufacturing processes, and the firm’s adherence to current good manufacturing practice.

The drugs that pharmacists compound (including compounded hydroxyprogesterone caproate) are not FDA approved, which means they do not undergo premarket review nor do they have an FDA finding of safety and efficacy. Compounding large volumes of drugs that are copies of FDA-approved drugs circumvents important public health requirements, including the Federal Food, Drug, and Cosmetic Act’s drug approval provisions. Consumers and health professionals rely on the Act’s evidence-based drug approval process to ensure that drugs are safe and effective. For that reason, one factor that the agency considers in determining whether a drug may be compounded is whether the prescribing practitioner has determined that a compounded product is necessary for the particular patient and would provide a significant difference for the patient as compared to the FDA-approved commercially available drug product.  

FDA emphasizes that it is applying its normal enforcement policies for compounded drugs to compounded hydroxyprogesterone caproate. The compounding of any drug, including hydroxyprogesterone caproate, should not exceed the scope of traditional pharmacy compounding. As the Agency has previously explained, FDA generally prioritizes enforcement actions related to compounded drugs using a risk-based approach, giving the highest enforcement priority to pharmacies that compound products that are causing harm or that amount to health fraud.

Independent Laboratory Testing Demonstrates Important Quality Differences Between FDA-Approved Makena® and Compounded 17P Formulations

 

 

FDA Issues Statement on Makena® on November 8, 2011

ST. LOUIS, Nov. 8, 2011 /PRNewswire/ -- Recent testing conducted by independent laboratories, commissioned by Ther-Rx Corporation, a subsidiary of K-V Pharmaceutical Company (the "Company") (NYSE: KV.A/KV.B), shows that multiple samples of both compounded 17P drug formulations and active pharmaceutical ingredient (API) that may be used in compounded 17P failed to meet certain established standards for potency and purity. These findings, which have been submitted to the U.S. Food and Drug Administration (FDA), demonstrate important quality differences in these compounded 17P formulations when compared to FDA-approved Makena® (hydroxyprogesterone caproate injection).

"We commissioned this research because moms and healthcare providers deserve to know whether medications prescribed during pregnancy meet FDA's quality standards," said Greg Divis, President and CEO of K-V Pharmaceutical Company. "This research demonstrates important differences in product quality between FDA-approved Makena® and these compounded 17P formulations. Healthcare providers and patients have no practical way of ensuring that compounded 17P formulations meet FDA's quality standards. Now that FDA-approved Makena® is available, America's high-risk moms deserve a product that consistently meets FDA's standards."

On Nov. 8, 2011, the FDA issued a statement on Makena® acknowledging it has received information from the Company regarding the potency and purity of samples of bulk hydroxyprogesterone caproate APIs and compounded hydroxyprogesterone caproate products. FDA stated, "According to the analysis of this information provided by K-V, there is variability in the purity and potency of both the bulk APIs and compounded hydroxyprogesterone caproate products that were tested." The agency has begun its own sampling and analysis of compounded hydroxyprogesterone products and the bulk APIs used to make them. In FDA's statement, the agency "reminds healthcare providers and patients that before approving the Makena® new drug application, FDA reviewed manufacturing information, such as the source of the API used by the manufacturer, proposed manufacturing processes and the firm's adherence to current good manufacturing practice. Therefore, as with other approved drugs, greater assurance of safety and effectiveness is generally provided by the approved product than by a compounded product."  

The full text of the FDA statement is available athttp://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm279098.htm

Overview of Research

The active pharmaceutical ingredient in FDA-approved Makena®, hydroxyprogesterone caproate, is sourced exclusively from the same FDA-registered and FDA-inspected manufacturer that supplied the API used in the NICHD study that served as part of the basis for FDA approval of Makena®. To the Company's knowledge, this is the only manufacturer of hydroxyprogesterone caproate known to have an active Drug Master File with the FDA.  

Research commissioned by Ther-Rx shows that the API used in compounded 17P formulations originates primarily from facilities in China that are neither registered with nor inspected by the FDA. This research also found that the vast majority of entities claiming to be original manufacturers of hydroxyprogesterone caproate are actually re-packagers, re-sellers, brokers or distributors of hydroxyprogesterone caproate that is actually manufactured in China.

The Company also commissioned independent laboratory testing to assess samples of API and compounded 17P formulations and, as such, does not purport to assess the quality of all of the various compounded 17P formulations and hydroxyprogesterone caproate API available on the market. Specifically, the laboratory testing included:

• 10 samples of API used in compounded 17P formulations provided by 10 different suppliers of API. Seven of the suppliers were determined to be original manufacturers of API that are located in China and that, to the Company's knowledge, do not appear to have been registered with or inspected by the FDA. The other three were identified as U.S.-based resellers of API, whose product is also believed to originate from China.
• 30 vials of compounded 17P formulations, prepared by 30 different compounding pharmacies across 15 states.

The independent laboratories measured the quality of each API sample and compounded 17P vial against certain quality standards required by FDA for Makena®. The samples also were evaluated by these labs against certain U.S. Pharmacopeia (USP) standards for hydroxyprogesterone caproate and hydroxyprogesterone caproate injection, because some compounding pharmacies claim that their compounded formulations meet USP criteria. The laboratories analyzed the API and compounded 17P drug formulations to assess potency, chemical impurities and drug identity.

Key Laboratory Testing Findings

Active Pharmaceutical Ingredient (API)

• One API sample sent from a Chinese manufacturing facility was not the correct active pharmaceutical ingredient. Although the package was sent to the United States labeled in Chinese as hydroxyprogesterone caproate (HPC), the active ingredient failed the drug identity test for HPC. Further laboratory analysis conclusively proved that the substance was glucose instead of HPC.
• 80 percent (8 of 10) of the API samples failed to meet at least one FDA standard for unknown impurities.
• 50 percent (5 of 10) of the API samples failed to meet the USP standard for potency.
• The paperwork (certificates of analysis) that arrived with API shipped from China was often missing or incomplete. Such gaps in paperwork can make it difficult to track back specific product to specific manufacturing facilities, which is critically important should a problem with the medication arise.

Compounded 17P Formulations

• 27 percent (8 of 30) of the compounded 17P vials tested failed to meet the USP standard for potency. The potency values of the compounded 17P vials ranged from just over half to a level more than 2.5 times the labeled potency. If these vials were administered to patients, some patients would not have received the dose of 17P that was reviewed and subsequently approved by FDA for safety and efficacy in this patient population. This variability in potency was comparable to those found in FDA's limited survey of compounded drug products conducted in 2006, which is available at:  http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm204237.htm
• 53 percent (16 of 30) of the vials of compounded 17P had levels of unknown impurities that exceeded at least one standard required by the FDA for Makena®. The potential toxic effects of these unidentified compounds in the intended patient population are unknown.  
• Taken together, two-thirds (20 of 30) of the compounded 17P vials failed to meet at least one USP requirement (a standard used by some compounding pharmacies) or at least one FDA quality standard required of Makena® for potency and/or purity levels. Information was not obtained regarding the sterility of, or potential presence of endotoxins in, the compounded 17P vials.  
• FDA-approved Makena® must meet FDA's quality standards before release for patient use.

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K-V prompts FDA Investigation into Compounding Pharmacies--Makena--API Source from China

K-V prompts FDA Investigation into Compounding Pharmacies--Makena--API Source from China

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