New FDA Interim Guidance for Human Drug Compounding Outsourcing Facilities

 In the USA, the compounding of medicinal products was not regulated very well. The compounding of medicinal products can be outsourced to specific compounders (Compounding Pharmacies) bypassing the authority and GMP regulations. Also quantitative limitations don't play any role so that those compounders could produce at industrial scale and thus also win a substantial share of the medicinal products market.

So far, they have been in a sort of no man's land in the USA. Manufacturers of medicinal products are regulated at federal level by the FDA, whereas pharmacies - including also Compounding Pharmacies - face a respective heterogeneous regulation at the level of the 50 federal states. In 2002, the Supreme Court refused FDA's attempts to intervene with regulations. 

The inglorious culmination of this situation was the case New England Compounding Center (NECC) in 2012. A steroid solution for epidural injection had a fungal contamination and had been administered to approx. 14,000 patients. About 50 patients died of meningitis and over 700 had to be treated against fungal infection.

In 2013, the regulations in the USA were adjusted - DQSA Pub. L 113-54 - to transfer to the FDA the monitoring of outsourced compounding facilities. The subsequent inspections with a lot of Warning Letters issued to the compounders (partly with outrageous quality deficiencies) clearly showed the consequences of inexistent inspections over many years.

The FDA has recently announced that it will regulate this area in the future in accordance with the cGMP. Until appropriate regulations have been developed, the FDA has - in the meantime - expressed its expectations for this transitional period in a Guidance for Industry - Current Good Manufacturing Practice - Interim Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act. This Guidance is based on the 21 CFR parts 210 and 211 with regard to cGMP. The FDA has tried to take into consideration the differences between industrial medicinal products manufacturing and compounding, and to adjust the specific aspects of the compounders. The FDA has announced that it will focus its inspections efforts to the points which present the highest danger for patient safety. One should thus not be surprised - also in view of the past incidents - that these efforts will particularly address the securing of sterility. Decidedly, the following topics are addressed:

  • Facility Design
  • Control Systems and Procedures for Maintaining Suitable Facilities
  • Environmental and Personnel Monitoring
  • Equipment, Containers, and Closures
  • Components
  • Production and Process Control (General Production and Process Control / Aseptic Drug Processing)
  • Release Testing
  • Laboratory Controls
  • Packaging and Labels
  • Quality Assurance Activities / Complaint Handling

One interesting thing is that the FDA itself isn't quite sure about certain aspects, whether its requirements will be suitable for compounders. In the chapters "Components" and "Laboratory Controls", an "Alternative Approach for Comment" is respectively presented in the Guidance to both topics "Reducing the Need for Laboratory Testing of Incoming Components" and "Minimize Need for Facilities to Have an In-House Laboratory".

All in all, this is an interesting development, and most of all has been a necessary evolution in the regulation of compounders which comes a few years too late.


Guidance for Industry - Current Good Manufacturing Practice - Interim Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act

Guidance - Pharmacy Compounding of Human Drug Products Under Section 503A of the Federal Food, Drug, and Cosmetic Act

Warning Letters to companies producing sterile drugs

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