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Robert G. Bell

Robert G. Bell, Ph.D., is president and owner of Drug and Biotechnology Development LLC.

On October 26, 2012, the FDA issued a Form 483 with five observations to the New England Compounding Center, the company at the center of the storm of the fungal meningitis outbreak associated with more than 400 cases reported in almost 20 states with 29 deaths. During the inspection, the FDA observed contaminated products and listed a number of deficiencies regarding conditions in the clean rooms, environmental controls, and quality procedures. You can view the complete FDA Form 483 here.

Good Manufacturing Practice (GMP) manufacture of sterile products and a pharmacy compounding “sterile” products are regulated differently—pharmaceutical manufacturing by Part 211, Title 21 of the Code of Federal Regulations (current GMP) with FDA enforcement versus compounding pharmacies by United States Pharmacopeia (USP) <797> “Pharmaceutical Compounding—Sterile Preparations” with state enforcement. The GMPs for the pharmaceutical industry assure the quality of a commercial drug product for interstate commerce through its listed shelf-life. Compounded sterile preparations (CSP) must be patient specific, based on a prescriber’s order, and the product administered typically within 12 hours of preparation.

USP <797> provides the minimumpractice and quality standards for compounded sterile preparations and is suitable for compounding sterile preparations in the appropriate pharmacy setting; however, it is not suitable for GMP production of large batches intended for interstate commerce. USP <797> regulations emphasize the need to maintain high-quality standards for processes, components, and environments for sterile compounding preparations. However, processes and conditions in a “sterile” pharmacy compounding practice are not usually validated; they usually possess adequate in-process controls and testing and are more susceptible to contamination when compared to GMP pharmaceutical manufacturing facilities.

This is evident from the issued FDA 483s. The first observation of the FDA 483 indicates that over 25% of the methylprednisolone vials evaluated visually contained “greenish black foreign matter.” Although sterility was assured by the company’s testing, 50 out of 50 vials tested by the FDA confirmed the presence of viable microbial growth and one vial examined microscopically showed fungal morphological features. The FDA noted that the firm’s environmental monitoring of the clean rooms had bacteria, molds, and overgrowth. These results were not investigated; no identification of the isolates were conducted; no product impact assessments were performed; and the firm has no evidence that any corrective actions were taken to prevent contamination.

The GMPs and Quality-by-Design principles associated with sterile pharmaceutical industry production help assure the identity, purity, potency, stability, and quality of the manufactured drug products through quality risk management, validation, controls, and testing. The USP states, “It is the ultimate responsibility of all personnel who prepare CSPs to understand these fundamental practices and precautions, to develop and implement appropriate procedures, and to continually evaluate these procedures and the quality of final CSPs in order to prevent harm and fatality to patients who are treated with CSPs.”

In this situation, the understanding and quality is lacking. Compounding pharmacies should not be operating as pharmaceutical manufacturers producing thousands of doses for interstate commerce—this does not comply with USP <797> or the GMPs and the quality and stability of the sterile compounded products cannot be assured.