Compounding Pharmacy


Historically, USFDA had chosen to exercise enforcement discretion with respect to compounding pharmacy operation, as these facilities were registered with and received oversight from the state Board’s of Pharmacy.  This changed in 2011.

The Drug Quality and Security Act legislation was written in response to the meningitis outbreak caused by the non-sterile compounding of drugs by the New England Compounding Center.  As reported by CDC, the actions of the New England Compounding Center resulted in the deaths of 64 individuals with a total case count of 751.

NECC1

Note: Persons with Fungal Infections Linked to Steroid Injections by State, Multistate Outbreak of Fungal Meningitis and other Infections – Case Count, CDC (October 2013), retrieved from http://www.cdc.gov/hai/outbreaks/meningitis-map-large.html

Public Law 113-54, Drug Quality and Security Act, was enacted November 27, 2013.  In summary, this Act defined outsourcing facilities, provided for registration of these types of facilities, and established FDA oversight and regulation for these activities.

A review of the FDA website identifies that Compounding Pharmacies have received warning letters since ~2005.  However, this post focuses on FDA inspection of Compounding Pharmacies after enactment of the Drug Quality and Security Act.  A review of FDA website identified that 40 Compounding Pharmacies have received warning letters following FDA inspection.  Approximately 210 citations attributable to failing to follow current Good Manufacturing Practices 21 CFR 210 and 211 were identified.  Of these:

Sixty-nine (69) citations were identified for violations of Subpart C, Buildings and Facilities, section 21 CFR 211.42, Design and Construction features.  Specifically:

  • Aseptic processing, which includes a system for monitoring environmental conditions (21 CFR 211.42(c)(10)(iv)), was identified 31 times.
  • Aseptic processing, which includes a system for cleaning and disinfecting the room and equipment to produce aseptic conditions (21 CFR 211.42(c)(10)(v), was identified 16 times.
  • Aseptic processing, which includes an air supply filtered through high-efficiency particulate air filters under positive pressure, regardless of whether flow is laminar or nonlaminar (21 CFR 211.42(c)(10)(iii)), was identified 9 times.
  • Aseptic processing, which includes a system for maintaining any equipment used to control the aseptic conditions (21 CFR 211.42(c)(10)(iv)), was identified 8 times
  • Adequate space as necessary to prevent mixups and contamination (21 CFR 211.42(b)) was cited 5 times.

Forty-four (44) citations were issued for Subpart I, Laboratory Controls, specifically:

  • Special testing requirements, which require test procedures for verification of sterility and/or pyrogen-free be both written and followed. 211.167(a) was cited 19 times.
  • Stability Testing, which require a written testing program to assess the stability of drug products (21 CFR 211.166(a), was cited 18 times.
  • Testing and release for distribution, which requires for each batch of drug product appropriate testing to prove conformance to final specifications including identify and strength of each active ingredient is completed prior to release (21 CFR 211.165(a), was cited 7 times.

Thirty-three (33) citations were issued for violations of Subpart F, Production and Process Controls, section 21 CFR 211.113(b).  This section addresses the need for appropriate written procedures to prevent microbiological contamination to be established and followed.  This also includes the validation of all aseptic and sterilization processes.

Twenty-four (24) citations were issued for Subpart B, Organization and personnel, section 21 CFR 211.28(a).  This part requires personnel to wear clean clothing appropriate for the duties they perform, and protective apparel such as head, face, hand, and arm coverings as appropriate to prevent contamination of drug products.

The above examples are not offered as an all inclusive list of FDA findings in Compounding Pharmacies.  Rather, the above examples are provided as a benchmark of the most frequent and typical, findings of Compounding Pharmacies that have received warning letters following FDA inspection.  Have you checked/ audited your facility?  How does your facility compare to these?