Aseptic Processing Contamination Case Studies and the
Pharmaceutical Quality System
Richard L. Friedman
Food & Drug Administration, Center for Drug Evaluation & Research, Division of Manufacturing & Product Quality
ABSTRACT: This paper summarizes parenteral drug contamination case studies presented at industry conferences and a Food and Drug Administration advisory committee meeting in the period of 2000-2004. CGMP deficiencies associated with each contamination event are discussed. The key role of a well-functioning quality system in contamination prevention is emphasized.
While many references (1–7) discuss principles of aseptic process control, fewer publications illustrate the practical impact of substandard production practices on a product purporting to be sterile. By examining case studies, the tangible consequences of a breakdown of one or more elements of current good manufacturing practice (CGMP) can be explored. (8.9)
Three prevalent themes are central to the vast number of aseptic processing contamination problems:
• poor personnel practice
• loss of environmental control
• flawed operational design
One or a combination of these CGMP deviations has led to contamination of aseptically processed products, including parenterals, ophthalmics, and aqueous inhalers (10, 11). While personnel practice or a loss of environmental control are normally named as the immediate source of a sterility problem, the investigation into root cause (12) frequently also concludes that changes in operational design are needed to implement a lasting solution.
Quality is built into a product produced by aseptic manufacture when sound process, equipment, and facility design is employed to minimize or eliminate potential contamination hazards. Modern design approaches include systematic evaluation of potential process vulnerabilities and holistic awareness of how daily dynamic operational factors can interact (13, 14).
This process understanding should lead to dependable design choices. The new process is then supported
throughout the product lifecycle by a robust quality system that provides the infrastructure for continuous improvement (15) and consistent contamination prevention in accordance with 21 CFR 211.42 and 211.113 (16).
The Quality System
Figure 1 is a diagram of six basic elements of a pharmaceutical operation, based on the finished drug
CGMP regulations (21 CFR 210 and 211). These interrelated elements are outlined in the Food and
Drug Administration’s (FDA’s) Drug Manufacturing
Inspections compliance program (17) and are known collectively as the quality system (18). As depicted by the diagram (19), a quality system provides the nucleus that drives the proper functioning of each of the five manufacturing systems. The quality system integrates all of these elements and its placement at the center is also meant to signify a sixth system of quality assurance (e.g., quality management, SOP review and approval, batch release). The case studies in this paper illustrate how drug product contamination stemmed from deficiencies in one or more system. This paper expands upon previously published contamination case studies (20) by emphasizing the single quality system element that appeared to be most deficient as the process drifted, generally undetected for a significant period, from its state of control.
Case Study 1: Aseptic Processing of a Sterile Active
Pharmaceutical Ingredient (API)
A sterile active pharmaceutical ingredient (API) manufacturer shipped numerous lots of an aseptically proPDA Journal of Pharmaceutical Science and Technology
dium and effects of residual medium on membrane filter).
• During process simulations, the firm dried the media at 85–95 °C. This temperature contrasted with the 20 –25 °C conditions used for the API process. The use of high temperatures for drying in the process simulation did not reflect the actual processing parameters. It might be expected that a