FDA recently published the Office of Compliance Annual Report for Calendar Year 2018. Their stated mission is “To shield patients from poor quality, unsafe and ineffective drugs through proactive compliance strategies and risk-based enforcement actions.” The Annual Report describes how they have fulfilled that mission in calendar year 2018, and we cover some of those activities below.
We take a look at some of the key compliance initiatives and actions in these areas in 2018. Among FDA’s highest priorities are actions taken to reduce the impact of the opioid crisis.
Actions taken within the Office of Compliance to address this nationwide problem include:
- Collaboration with internet stakeholder to remove sites from searches that have been the subject of warning letters citing misbranded and unapproved drugs for sale in the US.
- Collaboration with social media outlets to redirect those seeking to purchase opioids online to Substance Abuse and Mental Health Service Helpline.
- Issuing seventeen warning letters to firms offering misbranded and unapproved opioids for sale on their just under 400 websites.
- Jointly issued twelve warning letters in partnership with the Federal Trade Commission (FTC) and the FDA Center for Food Safety and Applied Nutrition (CFSAN) to firms that marketed opioid cessation products. These products are unapproved drugs and have not been through FDA review for safety and efficacy.
- Two additional warning letters were sent to manufacturers of homeopathic products claiming to treat opioid addiction.
Compounding Pharmacies and Outsourcing Facilities
FDA continues enforcement actions and policy activities in the area of compounding pharmacies and outsourcing facilities. While legitimate compounding pharmacies serve a necessary medical need, it is unclear to me what value the outsourcing facilities provide, particularly when considering the time and energy spent by the FDA in enforcement in this area.
Originally when the FDA sponsored the formation of these firms, it was thought they might be valuable partners in alleviating drug shortages. I have yet to see any evidence that this has been the case.
Actions taken by the FDA in this area include:
- Implement the compounding policy priorities plan which focuses actions on products of highest risk, primarily injectable dosage forms.
- Continue to issue compounding risk alerts, including those for sub-potent or super potent product, those for which sterility assurance cannot be guaranteed and adverse events associated with compounded products.
- Issued a revised Memorandum of Understanding (MOU) describing the partnership between state authorities and FDA.
- Conducted 128 inspections of compounding facilities.
- Issued 24 warning letters to compounding firms.
- Oversaw 24 recall events for compounded drugs, generally associated with a lack of sterility assurance or super-potent dosage forms that posed a serious health hazard.
- Participated with DOJ in two civil enforcement actions, particularly consent decree agreements.
Angiotensin II Receptor Blocker Recalls
FDA was alerted to nitrosamine contamination of the valsartan API by Zhejiang Huahai Pharmaceuticals, a company in Linhai, China. This API is supplied to many dosage form manufacturers.
Both EMA and FDA have conducted investigations of this ongoing, and expanding, event and associated recalls. Additional nitrosamine compounds have been identified in other ‘sartan’ products. Additional manufacturers of problematic API have been identified. In December 2018, FDA published ‘interim acceptable daily intake limits’ for nitrosamine impurities in this class of drugs.
While not in the 2018 annual report, the FDA issued a warning letter to Aurobindo that addresses the nitrosamine contamination and lack of adequate assessment of manufacturing changes, particularly solvent changes.
GDUFA II Commitments
FDA committed to inform manufacturers of the GMP status (NAI, VAI or the dreaded OAI) of their facility within 90 days of completion of the inspection. This was accomplished by sending firms with OAI (Official Action Indicated) status a letter stating such within 45 days after the inspection. The report states that the goal was met 97% of the time.
Highlights of the Office of Compliance activities regarding import alerts include:
- 45 facilities were added to the Import Alert 66-40 list for failure to meet GMP requirements.
- 24 facilities were added to Import Alert 99-32 for refusing to permit an FDA inspection.
The Office of Compliance also took action in a variety of other areas, including:
- Reminding consumers to avoid male enhancement products marketing as dietary supplements that contain active pharmaceutical ingredients and thus are unapproved new drugs.
- Working with international partners to collaborate on global enforcement activities.
- Ongoing evaluation of the future of the National Drug Code (NDC), particularly the future format.
- Sponsorship and participation in industry trade group meetings such as PDA.
Pages 23 through 26 of the report include a variety of tabulated information and accomplishments from 2018 including:
- A listing of documents, rules, and regulations published in 2018.
- A listing of safety notifications published in 2018.
- Engagement, including but not limited to, public meetings, meetings with industry, conference presentations and external training.
- Obtained five permanent injunctions with one action still pending, and one seizure for food and medical products.
- The distribution of CDER Class I, II and III recalled drug products from 2018; there is also a somewhat unusual table that I cannot figure out because it identified Class I, II and III “drug-related warning letters.” Perhaps FDA can clarify what they mean here.
- One clinical investigator disqualification.
- Tabulation of drug-related warning letters from a variety of Offices within the Office of Compliance. The total was 142 warning letters for the year with 84 issued by the Office of Manufacturing Quality. It would be nice to get some clarification on the other warning letters.
- And finally, in the last tiny table on page 26, FDA identifies that 30 of the 84 total warning letters include data integrity violations, for a total of 35 percent. Everyone who counts these, and many of us do, keeps track of this and get different, larger values than this number. It would be instructive to see a list of warning letters that the FDA has deemed to include data integrity violation. Note that the 84 warning letters do not include those issued to compounding pharmacies and outsourcing facilities. They clearly have their own problems!
A look ahead for 2019 sees FDA continuing the work on the 2018 priorities including impact on the opioid crisis, improving the quality of compounded medicines and will “…take regulatory and enforcement actions targeting compounded medicines with the greatest potential to cause patient harm.” Further, FDA will continue to implement the requirements of DSCSA moving toward a functional track and trace system that will permit FDA and others to “…rapidly respond when such medicines are found in the drug supply chain.” In a perfect world, actions could be taken to prevent such drugs from ever entering the system, or at least to remove them long before they reach patients.
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