ABSTRACT
Equipment used in pharmaceutical and biopharmaceutical production is vulnerable to varying degrees of microbial contamination that originate from many sources. An ineffective equipment-cleaning program can have many negative consequences, including the risk to patient health and quality of product manufactured that could in turn lead to product withdrawal from the market. It is therefore not surprising that cleaning validation undergoes extensive regulatory review in the pharmaceutical industry during inspections. In fact, during the past few years, cleaning validation has ranked among the top 10 areas of concern in warning letters issued by the FDA. According to Kristen Evans, leader of the Guidance and Policy Team in the Division of Manufacturing and Product Quality in FDA’s Center for Drug Evaluation and Research, equipment cleaning and maintenance ranked second in warning letters and GMP citations for the scal year (FY) 2004-2005 [1]. Although not all cleaning issues relate to microbial contamination, controlling bioburden through adequate cleaning processes is a regulatory expectation enforced by the FDA as illustrated in the following excerpts from two regulatory citations:
FDA 483 issued to Evans Vaccines (Merseyside, UK), an afliate of Chiron Corporation, regarding product sterility failure investigation in October 2004: “Cleaning validation for the CIP process for vessel … which is utilized in the aseptic formulation of trivalent bulk inuenza, did not include an assessment of sprayball coverage for the vessel. In addition, the study did not include swab sampling of the transfer lines used in the transfer of monovalent blend pools into the mixing vessel … and for transferring the aseptic trivalent formulated bulk back into a sterilized … liter tank in formulation room.” FDA warning letter issued to MedImmune Inc. (Gaithersburg, MD) on May 24, 2007, regarding bioburden deviations in the manufacture of bulk
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monovalent lots for FluMist vaccine during the 2006-2007 campaign: “Of particular concern are your inadequate investigations into such excursions, and your lack of implementation of appropriate corrective and preventative actions, coupled with deficiencies in: aseptic practices by personnel, cleaning validation of equipment and effectiveness of the cleaning and disinfection processes used in your manufacturing facility and by your personnel.”
Microbial contamination is a multiparametric process, which is affected not only by sources of contamination but also by the environmental conditions and properties of contaminated materials (e.g., surface charge, hydrophobicity, texture, etc.), which can contribute to microbial adhesion and proliferation. Although sterilization and sanitization procedures for equipment are beyond the scope of the FDA Guide to Inspections-Validation of Cleaning Processes, the FDA does address in this document concerns regarding control of bioburden in process equipment. Indeed, the FDA expects companies to have written procedures not only to prevent ingress of contamination but also to eradicate or reduce bioburden through validated sterilization and cleaning procedures. Ideally, production equipment used in the manufacture of drugs that will be rendered sterile should be sterilized (e.g., steamed in place or autoclaved) to prevent product contamination.
