FDA warning letters 2014 & 2015 – Finished Pharmaceuticals

USA FDA issues a warning letter to another compounding pharmacy

Compounding pharmacies are in the FDA’s headlights again, with another pharmacy receiving a warning letter after an inspection, these inspections normal have findings relating to poor design of pharmacy clean rooms, i.e. CFR 211.42.

Highlighted below within the text are the top 10 ranking 2014/15 FDA warning letters trends, full list here.

The Warning Letter included: “For example, the investigators noted that your facility is not adequately designed for sterile drug production. Specifically, your facility was not in a good state of repair as investigators observed the ISO 5 area contained peeling paint and dark yellow residues on the walls. In addition, your ISO 5 area is not separated from the ISO 7 area in a way that allows for adequate pressure differentials to be maintained between areas of different air classifications.”

The FDA Warning letter went on to say “Your facility lacks pressure gauges to monitor pressure differentials between the ISO 5 area and the ISO 7 area. In addition, gowning procedures are inadequate and allow for bare hands in the ISO 7 area. Investigators observed operators with exposed foreheads in the ISO 7 area. Moreover, your firm uses non–sterile disinfectants in the ISO 7 and ISO 5 areas and on the equipment. Furthermore, your firm failed to demonstrate through appropriate studies that the aseptic processing areas are able to provide adequate protection of the ISO 5 area in which sterile products are processed. Therefore, your products may be produced in an environment that poses a significant contamination risk.” 

The FDA warning letter included the following specifics:

“FDA investigators also noted CGMP violations at your facility, causing your drug product(s) to be adulterated within the meaning of section 501(a)(2)(B) of the FDCA.  The violations include, for example:

  1. Your firm failed to establish an adequate air supply filtered through high-efficiency particulate air filters under positive pressure in the aseptic processing areas. (21 CFR 211.42(c)(10)(iii)) 
  2. Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes. (21 CFR 211.113(b) Arguably similar to clause (a) Top 10 number #6 in 2014/15
  3. Your firm failed to ensure that floors, walls and ceilings in the aseptic processing areas are smooth and hard surfaces that are easily cleanable. (21 CFR 211.42(c)(10)(i)) 
  4. Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas. (21 CFR 211.42(c)(10)(iv)) Top 10 number #1 in 2014/15
  5. Your firm failed to ensure the system for cleaning and disinfecting equipment is adequate to produce aseptic conditions. (21 CFR 211.42(c)(10)(v)) Top 10 number #3 in 2014/15
  6. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed. (21 CFR 211.192) 
  7. Your firm failed to adequately design the facility with adequate separation or defined areas or such other control systems necessary to prevent contamination or mix-ups. (21 CFR 211.42(c)) 
  8. Your firm failed to ensure that manufacturing personnel wear clothing appropriate to protect drug product from contamination. (21 CFR 211.28(a)) Top 10 number #4 in 2014/15


Pharmacy clean rooms contamination risk – design it out

Citations for contamination risk in pharmacy clean rooms are still in the top most common inspection findings by the US FDA in 2014/15, (read the summary of these findings)  and the MHRA in recent years. As David Churchward, Expert GMDP Inspector, stated last year at an ISPE conference, the contamination citations are based on the “old” EU GMP, this is before the more recent changes to Chapters 3 and 5 which include new or enhanced cross contamination guidance.

nic van der nol

Contamination risk certainly weighs heavily in my mind when I design Compounding Pharmacy Cleanrooms,” said Nic van der Nol, Executive Architect at PharmOut. “I’m continually frustrated that even rudimentary design reviews are not done. When I speak to the students I lecture at Melbourne University, I drum into their heads that once the concrete is poured the cost of a change increases a thousandfold,” he went on to say.

Fortunately, Nic is surrounded by a number of very experienced cleanroom engineers and GMP experts who have successfully guided many private, state and government cleanroom facilities through regulatory approval. More importantly, those engineers have a pharmacy and/or factory production background, so know how to incorporate Lean and cost-effectiveness into the cleanroom design.

Regretfully, the US cleanroom design engineers who designed the facility at the Compounding Pharmacy mentioned above do not have exclusivity on poor design. I saw many design issues during my recent travels into Asia and the EU.

Observations of poor design (in no particular order), included:

  • placing passive pass-through boxes between Grade D and B rooms
  • not having any consideration of the recovery times for the clean rooms, or low level returns
  • installing dishwashers in Grade B rooms
  • having doors to black mechanical services areas from the Grade B clean room
  • the presence of exposed wood in a Grade C clean room
  • coffee cup rings in a Grade C cytotoxic suite, indicating beverage consumption in the room

One of the engineers at PharmOut recently commented that he is constantly amazed that “bridge builders” are designing and building pharmaceutical clean rooms. He noted that a Compounding Pharmacy clean room is a highly specialised and engineered facility and, in the case of sterile and aseptic processing, designed to keep patients safe.

If you would like know how to correctly design a clean room, why not attend the National Validation and GMP Forum on the 11th and 12th July in Melbourne Australia,

  • Gordon Farquharson’s, Sterile Manufacturing Training on the 13th July, Gordon will be supported by Laftech, LAF Technologies is one of Australasia’s leading suppliers of controlled environment systems and instrumentation that could help you avoid the #1 USA FDA warning letter finding in 2014/15.
  • Roy Cherris will be sharing his experiences in a Visual Inspection Training Course on the 13th July. Professional activities have included various PMA, PDA technical committees including the PMA-USP <788> Revision Task Group and PDA Visual Inspection Task Force, ISPE.

Read more related posts here and here.