Contaminated LVPs and the Origins of Validation 1

The year 2006 marked the 30th anniversary of the formal introduction of process validation concepts and requirements by the US Food and Drug Administration. Despite more than 30 years of common usage, only recently have the theory and practice of validation become fully developed and widely understood, although many misconceptions remain.
Origins of validation

Milestone. 30 Years of Pharmaceutical Technology
The concept and practice of pharmaceutical validation first became law in June 1963 with the publication of good manufacturing practice (GMP) regulations. Before that, there was no requirement to validate production processes. Product quality was presumably ensured by collecting and analyzing drug samples. Despite the law, there remained little inspectional focus on process validation. This changed, however, when a nationwide epidemic of septicemia occurred that was caused by contaminated intravenous fluids (large-volume parenterals, LVPs). Between July 1970 and April 1971 in many hospitals in the United States, there were outbreaks of nosocomial (hospital acquired) septicemia caused by Enterobacter cloacae or E. agglomerans. All of these hospitals used infusion products made by one manufacturer, and all affected patients had onset of septicemia while receiving the company's infusion products.

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Septicemia was epidemiologically and microbiologically traced to intrinsic contamination of the company's screw-cap closure for infusion bottles, which were sealed with a newly introduced elastomer liner. Investigations in the laboratory and in the manufacturing plant into the mechanism of contamination of these products revealed the following:
  • Epidemic strains were present in numerous areas throughout the manufacturing plants
  • Viable microorganisms gained access to the interior of screw-cap closures after the autoclave step of production
  • Cooling closures actively drew moisture through the thread interstices into the inner-most depths of the closure
  • Transfer of contaminants from closures to fluid was easily effected by simple manipulations duplicating normal in-hospital use (1).
Nine deaths were initially attributed to this outbreak. Further analysis estimated that between 2000 and 8000 cases had actually occurred. Not all cases ended with the death of a patient. Nonetheless, nearly 10% of the case patients in the studied hospitals died while bacteremic or shortly thereafter (2).

Milestone. 30 Years of Pharmaceutical Technology
On closer examination, FDA, the Centers for Disease Control and Prevention (CDC), and company officials discovered several manufacturing problems. Although component bioburden (bottles, caps, etc.) was acceptable pre- and poststerilization, product cooling and additional downstream processing were identified as the sources of contamination. Sterilizer cooling water was considered a possible source of contaminants. Water for bottle cooling was obtained from a municipal source, and chlorine content was frequently below that required for bacteriostasis. As bottles continued to cool after removal from the sterilizer, ambient air and moisture infiltrated through the bottle threads and into the cap liner. Disassembly and testing of cap inner components later demonstrated that environmental contaminants, including the epidemic organisms, were distributed within the caps. Bottle breakage was commonplace after sterilization, and dextrose solutions were spilled onto floors below conveyors and related equipment. Spillage actively promoted the growth of the epidemic organisms, creating a high bioburden in critical processing areas (1).

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