by Barbara Unger, GMP Quality Expert, and GMP Regulatory Intelligence Editor-in-Chief
July and early August 2017 saw another uptick in FDA actions associated with compounding pharmacies/outsourcing facilities. In the past few years, the FDA has placed a disproportionate effort towards enforcement actions for these facilities. We have addressed this focus and the history of these facilities in a previous blog. The FDA published twenty-one (21) 483s and six (6) warning letters issued to these facilities in July 2017. It’s clear that FDA’s extreme focus on these facilities continues and the compliance problems for these facilities have not been appropriately addressed. And, more problematic for me, is that firms do not appear to be learning from the enforcement actions taken against others in this area. In addition, there have been several recalls of unexpired products and notices to healthcare professionals regarding adverse events apparently associated with these products and two consent decree agreements. Let’s look at these in turn:
- On July 25, 2017, an FDA post identified a voluntary recall of all lots of unexpired sterile compounded products by Cantrell Drug Company. The firm is registered as an outsourcing facility. The reason for the recall was lack of sterility assurance. The firm received a warning letter on January 21, 2015, based on the outcome of an inspection ending November 4, 2013. The warning letter identified basic deficiencies in aseptic manufacturing practices. Further, the firm did not receive patient-specific prescriptions for their products. At the time the letter was issued, the firm was registered as an outsourcing facility. A search of the FDA’s Enforcement Report identifies thirty-four (34) product recalls for: sub-potent drugs (Class I and Class II), stability data not supporting expiry (Class II), and lack of sterility assurance (Class II). The most recent 22-page 483 posted on the FDA web site is based on an inspection ending October 14, 2016. The observations cited include, but are certainly not limited to: media fills that were not representative of the batch size, worst case or most challenging conditions, deficiencies in aseptic practices and disinfection of ISO 5 hoods, failure to validate sterilization process, and facilities not maintained in a clean state.
- On July 28, 2017, the FDA alerted healthcare professionals of adverse events associated with the use of triamcinolone and moxifloxacin for intravitreal injection compounded by Guardian Pharmacy Services in Dallas, Texas. Adverse events were reported to the FDA on April 5th and June 1st. At least forty-three patients received follow-up evaluation for a variety of symptoms and vision problems. Some problems did not appear until one-month post administration. While some patients improved over the 5-month follow-up period, the FDA reports that “a number of patients” continue to experience significant vision problems. The press release concludes by stating: “Compounded drugs have not been reviewed by FDA for safety, effectiveness, and quality. Although compounded drugs can serve an important medical need for certain patients, they also present risks to patients.” The FDA also published the 9-page 483 from an inspection of the Dallas site ending October 21, 2016. Observations identify problems with aseptic processing, complaint investigations, inadequate equipment and facility cleaning and maintenance, media fills that do not mimic actual production, and failure to validate sterilization processes.
- On August 4, 2017, the FDA posted an announcement on their website addressing the compounded curcumin emulsion product for injection from ImprimisRx in Irvine, CA. The patients “…reportedly experienced immediate hypersensitivity reactions.” The posting identified serious adverse events (including at least two deaths) and the information that ImprimisRx recalled all unexpired products that contained the ungraded component PEG 40 castor-oil on June 23, 2017. The FDA states that their investigation into these adverse events provide further support for their position that compounded drugs pose more potential risks to patients than those made by pharmaceutical companies. In this case, the FDA identifies the following risks:
- “The absence of a label warning about hypersensitivity reactions associated with the PEG 40 castor oil;
- The use of an ungraded inactive ingredient, i.e., PEG 40 castor oil, that is not suitable for human consumption or therapeutic use and may contain impurities such as DEG; and
- The IV administration of curcumin, even though its safety profile by this route of administration has not been established, nor has its effectiveness in treating eczema or thrombocytopenia.”
Further, the FDA investigation identified that the vial of product contained less than 2% of the concentration of active ingredient on the label, and the residual in the IV bag administered to one of the patients contained approximately 1% of the concentration of the material intended to be administered. The FDA states that “The ungraded PEG 40 castor oil in ImprimisRx’s curcumin emulsion product may have contained components that resulted in the hypersensitivity reactions. Castor bean seeds and pollens are known to be associated with hypersensitivity reactions. Food grade castor oil is processed to remove the potentially allergenic castor bean constituents, but ungraded PEG 40 castor oil may not be allergen-free. In addition to allergens, other potentially harmful contaminants and impurities could be present in the ungraded PEG 40 castor oil.”
The most recent inspection of the site in Irvine, CA ended on March 31, 2017 and resulted in a 3-page 483 available on the FDA website.
It is interesting that the firm’s website identifies quality standards that they claim to meet, but they do not include drug CGMPs from 21 CFR. Rather, it identifies only USP <795> and <797>. The do cite the Drug Quality & Security Act of 2013 which states that outsourcing facilities must comply with CGMPs, but do not mention that they either meet or exceed these standards. The firm’s website provides this information on their operation. The ImprimisRx site in Folcroft, PA received a 9-page 483 at the end of an inspection on August 1, 2016. The establishment type is identified as a producer of non-sterile drugs.
- An FDA press release from August 4, 2017 reports that Isomeric Pharmacy Solutions of Salt Lake City, Utah and two of the firm’s co-owners entered into a consent decree agreement with the courts. “According to the complaint for permanent injunction, Isomeric manufactured and distributed purportedly sterile drug products, including injectable and ophthalmic drugs that were adulterated because the drugs were made under insanitary conditions and in violation of current good manufacturing practice requirements under the FD&C Act.” The firm is registered as an outsourcing facility. They conducted a nationwide recall of all products within expiry between October 4, 2016 and February 7, 2017, based on the lack of sterility assurance. The firm is an outsourcing facility. HERE is the complaint filed in the courts.
The firm received a warning letter on December 12, 2016 that identified eight (8) basic deficiencies found during multiple inspections of the facility. The most recent inspection ended on March 24, 2017 and resulted in a 15-page 483.
- The United States and the owners, quality manager, and pharmacist of Medistat RX LLC of Foley, Alabama entered into a consent decree agreement. The firm is registered as an outsourcing facility in 2014 and notified the FDA that they ceased operation in October 2015. The firm is prohibited from manufacturing, holding, or distributing drugs until they comply with the FD&C Act and associated regulations and requirements. The FDA press release from July 6, 2017 describes the holding of drugs under unsanitary conditions and the enforcement actions that the FDA took prior to this agreement.
The FDA identifies that the most recent inspection of the site ended September 23, 2015 and resulted in a 7-page 483.
Clearly compounding pharmacies provide a necessary service in specific situations such as where patients have allergies to excipients in commercial products and need an alternative dosage form (i.e., where patients cannot swallow tablets or capsules). However, as shown in the cases above, these firms pose more risk to patients, particularly in their manufacturing of sterile injectable products, than do those made by pharmaceutical firms. Healthcare providers and the public would be well advised to take this into consideration when making medication decisions. The lower price that many of these firms advertise sometimes comes at its own cost. These were certainly not the only serious situations with outsourcing facilities or compounding pharmacies in the past few years. Among the most recent stories on this topic have been those associated with fungal meningitis tied to the use of a drug compounded by the New England Compounding Center. I continue to hope that the FDA will either publicly identify the value that this new class of facilities provides or, perhaps, severely curtail their activities, particularly in the compounding of sterile injectable products, in support of protecting the public health.
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