Over the past several years, the FDA has cited a number of Compounding Centers for compromised aseptic processing. Often this has resulted in only a Form FDA 483. In other cases the actions have resulted in both a Form FDA 483 as well as a subsequent Warning Letter. The Johnson Memorial Cancer Center is one of those that has been cited for both through a 483Â and a Warning Letter.
The following represents a summary of the FDAâs 483 and Warning Letter with some additional comments on my part.
The U.S. Food and Drug Administration (FDA) conducted an inspection of the Johnson Memorial Cancer Center, located at 142 Hazard Avenue, Enfield, CT 06082-4520 from July 16, 2014, to August 5, 2014.  During the inspection, the investigators observed serious deficiencies for producing sterile drug products, which put patients at risk. For example, the inspectors observed insanitary conditions such as filth, chipping paint, water stains in the ceiling within the classified ISO 7 preparation space, dirty equipment, and discoloration by a contaminant of unknown origin on HEPA filters used to filter air in the classified area where compounded sterile drug products are prepared. Deficiencies with environmental monitoring were observed to include the lack of microbial identification, lack of testing in the hoods within the rooms, and inadequate differential pressure monitoring. The FDA believed the products may be produced in an environment that poses a significant contamination risk. They (the FDA) subsequently issued a Warning Letter (Click Here) (October 28, 2015) which is highlighted in the following paragraphs.
Adulteration ChargesÂ
The FDA investigator observed that the sterile drug products were prepared, packed, or held under insanitary conditions, whereby they may have become contaminated with filth or rendered injurious to health.  Examples of insanitary conditions observed during the inspection include:
- Your firm recovered 55 environmental monitoring results of mold, 1 cfu and above, from classified ISO 7 areas (surface and air) during the reconstitution of sterile injectable drugs. In addition, you have not provided evidence that a health hazard evaluation was conducted to assess the potential quality impact of isolates present during aseptic processing of drug products intended to be sterile.
- Your firm had filth, chipped paint, water stains and unsealed openings in the ceiling drop tiles of your ISO-classified rooms, allowing non-HEPA filtered air to enter into these rooms from the plenum.
- Your firm did not provide evidence to demonstrate that environmental monitoring occurs within the ISO 5 hoods where drugs intended to be sterile were produced. You provided no assurance the cleaning, disinfecting, personal hygiene and garbing practices create a microbial environment within the aseptic processing areas that is suitable for the production of drug products intended to be sterile.
COMMENTÂ
Microorganisms (mold) isolated from the ISO Class 7 environment was not speciated. Speciation of such organisms would be helpful to determine the source and whether any cleaning or disinfection was effective in removing the source. In addition, it appears that no environmental monitoring was obtained from the ISO Class 5 hoods. The FDA Guidance for Industry for Aseptic Processing (Sept 2004), USP<1116> and Annex 1 Manufacture of Sterile Medical Products (revised, March 2009) highly encourage microbiological monitoring within the ISO Class 5 area and also to at least initially identify the microorganisms within an ISO Class 7 environment.
- Your firmâs pressure differentials between the anteroom and the uncontrolled office space were minimal, which creates the risk of dirtier air mixing with cleaner air within the aseptic processing areas.
- Personnel monitoring is limited to the assessment of the pharmacy technicianâs fingers, and this sampling is only done on an(b)(4) basis.  There is no assurance that hygiene practices were consistently suitable to prevent microbial contamination during the production of drug products intended to be sterile.
- Investigators observed dirty equipment noting yellow discoloration on the chemotherapeutic roomâs HEPA filters used to prepare sterile drug products and you took no corrective action.
COMMENTÂ
Observations 4, 5 and 6 represent very basic issues within an Aseptic Processing Area. While no numbers were provided for the pressure differentials between the anteroom and the uncontrolled office space, the fact that they had an anteroom, but yet the FDA was concerned with pressure differentials, suggests that the differential was not even 0.05 inches since even that minimal differential can eliminate the risk of dirty and clean air mixing.Â
Personnel monitoring should be a routine event upon the exiting of a Biologic Safety Cabinet. The sampling of the technicianâs fingers at an unknown frequency, without including at least the forearms, suggests that the Quality function did not understand the purpose of personnel monitoring.
As such, all sterile products you manufacture are adulterated within the meaning of section 501(a)(2)(A) [21 U.S.C. § 351(a)(2)(A)] of the FDCA. It is a prohibited act under section 301(k) of the FDCA to do any act with respect to a drug, if such act is done while the drug is held for sale after shipment in interstate commerce of the components used to make the drug and results in the drug being adulterated.
Corrective Actions
As noted previously, your firm ceased on-site sterile drug production operations, and during the inspection, you informed FDA investigators that the firm would voluntarily transfer all patient treatment activities to your main hospital.
However, we also note that your firm committed to FDA in its August 21, 2014 response to the Form FDA 483 (Click Here) to correct the above deviations listed in the Form FDA 483 and indicated your intention to resume production of sterile drugs. If you decide to resume production of sterile drugs, FDA strongly recommends that your management immediately undertake a comprehensive assessment of your operations, including facility design, procedures, personnel, processes, materials, and systems. In particular, this review should assess your aseptic processing operations. A third party consultant with relevant sterile drug manufacturing expertise could be useful in conducting this comprehensive evaluation.
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