An ASTM workshop and subcommittee (ASTM F04.15.17) focused on the cleanliness of synthetic, implantable biomedical devices took place in early May, 2003 in Kansas City, MO. The workshop was impressive in terms of the all encompassing, positive participation by 50 attendees. The following comments and questions at the workshop and committee meeting are illustrative of the dynamic, spirited interchange and of the complexity, and challenge of developing cleanliness standards for critical applications.
Defining Zero Contamination This is related to the perennial question “how clean is clean?” Many commentary indicated that it is impossible to define zero contamination. Just as zero contamination is not readily demonstrable, appropriate cleanliness is likely to be application-specific.
Benchmarking There is growing enthusiasm for determining how clean is clean enough by measuring residue on parts with a good history of clinical success. This benchmarking process is analogous to the concept of normal range or reference range in clinical chemistry, where healthy individuals are used to established desirable blood levels of a given analyte. However: what is healthy? What is a successful clinical history? Any consortium would need to identify both immediate biological inflammatory responses and longer-term, less-obvious, and perhaps more insidious responses to contamination.
Cross-fertilization of Technology Some approaches to cleanliness, contamination control, and acceptable contamination levels used historically in clean industries or for critical applications are likely to be adaptable for medical devices. Conversely, one would expect standards and approaches to setting standards to be adaptable to critical areas of manufacturing such as aerospace.
Identifying Cleaning Steps; Sources of Contamination We need to more clearly identify manufacturing steps which actually minimize contamination, whether or not they are termed cleaning steps. Seemingly non-critical processing and machining materials may contribute to contamination or to surface quality. Contamination can also occur after the manufacturing process from packaging, and plasticizers or lotions added to surgical gloves.
Sterility Versus Cleanliness Sterility must be distinguished from cleanliness. The contribution of formerly living (but no longer viable) materials to inflammatory responses and/or long-term performance can be significant. Endotoxins, lipopolysaccharides which are remnants of the cell walls of gram-negative bacterial cell walls, are non-viable, biological-based potential sources of contamination. Although once part of living cells, they are not removed by autoclaving.
Defining the surface in discussing surface contamination, how do we define a surface? Even seemingly impervious surfaces may exhibit porosity or cracking at the micro-level. Contamination can gradually “leach out” of underlying layers.
Extraction and Analysis of Contaminants Extracting, identifying, and quantifying adherent soils is increasingly of concern, particularly where the product must perform reliably for long periods of time. In addition, it is recognized that there are benefits and limitations of location-specfic microanalysis versus extractive analysis of the entire object. However, if extraction is chosen, what is a reasonable representative sample? How should larger objects be extracted? Given the number of steps in many device manufacturing processes there is the problem of the unexpected residue. What if an unexpected residue is discovered? How does one plan for unexpected residue?
Immediate Plans The committee is currently developing a series of analytical test standards. First, standards for quantifying and characterizing contaminants are developed. Ultimately, acceptable cleanliness levels will be developed. The committee meeting focused primarily on extraction techniques. Some issues include ultrasound versus refluxing, the choice of organic solvent or water, and other specific concerns in extraction technique such as numbers of parts to be extracted and specifics of beakers.
The Near Future The key to development of encompassing consensus standards is participation by a range of knowledgeable, interested parties. The next meeting of the F04 committee is scheduled for November 20, 2003 in Tampa Florida; and a symposium is scheduled in 2005. Now is the time to become involved in this important effort. We’ll keep you posted on progress in future columns.
The authors wish to acknowledge the input of Steve Spiegelberg, Polymer Technology.
Kanegsberg and Kanegsberg, Dead Dirt and Bio-Dirt, A2C2, April, 2003.
Note: Additional information regarding the F04 committee, the workshop, and copies of some presentations (including one by B. Kanegsberg) can be obtained at: http://www.campoly.com/cleanliness.html