When allowable, alternative approaches to batch testing can provide cost-saving opportunities to a medical device manufacturing company. Alternatives can reduce the number or frequency of samples tested. A key area for developing the rationale for alternatives to batch release testing is in the medical device manufacturing operation. According to the ANSI/AAMI ST72: 2002 recommended practice document, the design, validation, and control of the manufacturing operation are the three areas that need to be evaluated.¹ Before satisfying the qualification or validation activity for a medical device manufacturing operation, a manufacturing process risk analysis should be conducted. This analysis should identify key process steps or control points using a process risk assessment tool. One effective process risk assessment tool is the failure mode and effects analysis (FMEA).^2,3 This approach, as outlined in this article, enables medical device manufacturers to successfully conduct an analysis of bacterial endotoxin risk for a dry medical device manufacturing process. The FMEA can be used as a supporting document toward the development of the rationale for alternative batch release testing.

The FMEA Approach 

FMEA is a prevention tool used to assess, manage, and reduce risk associated with failure or potential failure of products, processes, services, and other systems.² This approach is summarized in the flowchart in Figure 1. This particular FMEA was used to assess, manage, and reduce the risk associated with the failure or potential failure of a manufacturing operation or process, with the goal of preventing bacterial endotoxin contamination from occurring during manufacturing. It also assessed the causes and effects of bacterial endotoxin level on the finished product. The bacterial endotoxin contamination cause-and-effect model is shown in Figure 2. The model illustrates the FMEA risk assessment concept. 

Manufacturing Operation Steps

FMEA can evaluate the manufacturing operation steps that could affect the bacterial endotoxin level on finished dry medical products and assess the likelihood of such contamination. Key manufacturing operation steps or control points may include, but are not limited to, the following:^4-6

•Raw Materials. Any incoming raw materials or components, manufactured on-site or supplied from an external vendor, that might pose potential endotoxin contamination risk to the manufacturing operation.
•Extrusion Operations. High-temperature products or components extruders where use of any uncontrolled water source to cool the extruded products or components might pose potential endotoxin contamination risk to the manufacturing operation.
•Washing, Leaching, and Soaking of Parts and Components. Use of uncontrolled water or solution sources that may pose an endotoxin contamination risk potential to washed, soaked, or leached products or components. 
•Drying and Curing Processes. Uncontrolled ambient or room-temperature drying of wet product or component surfaces, or uncontrolled curing processes. 
•Product, Part, and Component Handling. Potential endotoxincross-contamination risk associated with handling of products parts, or components during the manufacturing operation.
•Manual versus Automated Manufacturing Assembly Operation. The degree of direct human handling or contact—a potential source of endotoxin cross-contamination of products, parts, or components during the manufacturing operation—involved in various types of manufacturing operations.
•Product and Materials Storage. Storage of product, especially of materials that can support microbial growth prior to sterilization, and storage or plant environment conditions that promote microbial growth prior to manufacturing or sterilization.

All components and raw materials used to produce the final dry medical devices for a manufacturing operation will carry some degree of risk associated with failure of that product in the field. Although such risk can never be completely eliminated, it can be assessed, managed, and reduced through the use of an FMEA study.

In FMEA terms, risk may be defined in terms of occurrence (O), severity (S), and detection (D). Any risk, therefore, can be minimized if occurrences  decrease, the severity of the effect decreases, and the level of detection increases. 

Applying FMEA

This FMEA was conducted on an automated manufacturing operation for manufacturing dry disposable sets. The analysis process began with identification of the FMEA descriptions, the team members, and key manufacturing operation steps. Any up-front information obtained about the manufacturing operation can increase the efficiency and accuracy of the FMEA study. Up-front information can include:

•Past or current FMEAs for the manufacturing operation.
•Quality data or complaints about the manufacturing operation or finished product.
•Manufacturing operation control reports.
•Historical bacterial endotoxins test results and trends.
•Manufacturing operation flow- charts.
•Other key process data.

The risk assessment outlined in Tables I–III was not intended to cover all types of failure modes for this manufacturing operation. It addressed only the failure mode for the introduction of bacterial endotoxins into the manufacturing operation.

An FMEA should be conducted as a team activity. Team members from quality management, manufacturing engineering, sterility assurance, and process operation were selected to conduct this particular FMEA. 

There were several key operation steps, or control points, for this dry disposable medical device set. These key control points were identified as:

•Injection molding. 
•Plastic tubing extrusion. 
•Subassembly of the molded components and parts.
•Plastic sheeting forming and cutting. 
•Part molding and welding. 
•Automated assembly of the components and parts.
•Manual rework and repair of disposable device sets.
•Equipment maintenance.

An FMEA was conducted for each control point. This article focuses on the injection molding process to illustrate the FMEA approach. The first step involved identification of the potential failure mode, the potential effect of the failure, and the cause of the potential failure of the molding process.
In the injection molding step, raw materials are processed to create the molded components needed for manufacturing the dry disposable set. These components are manufactured by injecting 350ºF plastic into molds in a Class 100,000 controlled environment. The newly molded components are 
visually inspected and packaged into plastic bags in the controlled-environment area. Upon exiting the controlled environment, the bags are placed in cardboard boxes for transportation to the disposable set production area through the plant warehouse environment.

Several potential risk or failure modes involving bacterial endotoxins were associated with injection molding and the various functions of this process. These modes included bacterial endotoxin cross-contamination of molded components during transfer to inspection, manual handling of molded components or packaged molded components, and bacterial endotoxin contamination on the outside of the plastic bag or cardboard box from the plant environment.

The causes of the potential failure modes were bacterial endotoxin transferred from equipment surfaces, improper personnel cleanliness (wet hands), and water from the plant environment. The main effect of the failure modes was bacterial endotoxin cross-contamination onto molded component parts (see Table I).

Ratings and Priority Numbers

The next step was identifying occurrence (O), severity (S), and detection (D) ratings and calculating risk priority numbers (RPNs).

Ratings. Occurrence (O) refers to the probability that a specific cause will result in a specific failure mode. The qualitative rating scale for determining the occurrence rating is shown in Table II(a). It is important to note that the term failure does not refer to a bacterial endotoxin limit failure in the finished product (i.e., for a nonintrathecal device, the USP compendia endotoxin limit is not more than 20 endotoxin units (EU) per device⁷). The term failure in this case refers to the probability of the specific failure mode occurring. The introduction of bacterial endotoxins during the manufacturing operation may not necessarily cause the final medical device to fail the endotoxin limit requirement for that device. Also, bacterial endotoxin introduced to the exterior of the device will not affect a device that has a sterile, nonpyrogenic fluid path label claim. It also will not affect the device if the cumulative amount of the bacterial endotoxin contamination throughout the manufacturing operation is significantly below the endotoxin limit of not more than 20 EU per device. 

Severity (S) refers to an assessment of the seriousness of a failure as it affects the end-user. A higher severity rating was assigned to process steps that involved manual or machine contact with components or surfaces and were part of the sterile, nonpyrogenic fluid path of the final device product. The higher rating is necessary because introduction of bacterial endotoxins during these steps will result in a higher risk of introduction of bacterial endotoxins to the end-user. It is important to note that the introduction of low levels of bacterial endotoxins into a sterile, nonpyrogenic fluid path of a device may not cause adverse pyrogenic reactions to the patient. The qualitative rating for determining severity is shown in Table II(b). 

Detection (D) refers to the ability to detect the failure mode for bacterial endotoxin contamination risk prior to the customer receiving the finished medical device. The qualitative rating scale for determining the detection level is shown in Table II(c). 

Using these three rating scales, the FMEA team reviewed the list of potential causes generated for the injection molding process and estimated the likelihood of occurrence, severity, and detection by consensus with an assigned numerical rating from 1 to 5 (see Table I).

The risk level of each potential cause of failure is obtained by multiplying the likelihood of occurrence (O), the severity level (S), and the likelihood of detection (D) to obtain the RPN (RPN = O ¥ S ¥ D). This calculation should be performed after all the key steps and functions have been identified and analyzed. With this information, the FMEA team can determine the minimum RPN at which corrective action or justification is required.
Priority Numbers. To minimize bacterial endotoxin contamination risk for raw material processing of molded components, it is critical to determine and review the RPN rating. It is also essential to define planned controls, implement corrective actions (if needed), and recalculate the RPN (if required). Further review may be required when an RPN value exceeds 27 (3 ¥ 3 ¥ 3), or when any item is assigned a severity level of 5. 

Sometimes it is helpful to review the top 10–20% of the identified key functions. The FMEA team or appropriate management can decide the cutoff, based on the acceptable risk level for the manufacturing operation.

Corrective actions should be taken to address potential causes of failures that have severe effects, a high rate of occurrence, and low levels of detection. A new RPN value can be calculated after the corrective actions have been implemented. This new calculation is used to determine whether the new RPN value is below the cutoff value for acceptable bacterial endotoxin contamination risk to the manufacturing operation.

For this FMEA example, it was decided that a corrective action would be required only if the RPN value for any of the identified potential causes of failure was more than 20. In this case, the calculated RPN values for each of the identified potential causes of failure in the injection molding step and functions were all less than 20. Therefore, no corrective actions were needed for these potential causes of failure for this key step in the manufacturing operation. The current or planned controls for raw material processing of molded components were found adequate; they are identified in Table III. 

Documentation

The documentation of the FMEA can be analyzed using either paper or electronically generated worksheets. This particular FMEA study was documented as a risk assessment protocol and final report with the appropriate signature approvals. The protocol and report are kept on file at the 
manufacturing facility.

The FMEA is a living document, and it requires periodic reviews and updates to maintain a good documentation trail and change control. Document change control is needed to capture any significant changes to the current manufacturing operation and should trigger a review of the existing FMEA file. The FMEA and its associated documentation file must be revised to reflect any significant changes in the existing automated manufacturing process for manufacturing dry disposable sets. 

Conclusion

FMEA can be used as an assessment tool to identify potential risk associated with bacterial endotoxin contamination in a medical device manufacturing operation. The approach outlined in Figure 1 can enable medical device manufacturers to successfully conduct an FMEA for bacterial endotoxin contamination risk for dry medical device manufacturing operations. FMEA can be used as a supporting document toward the development of the rationale for an alternative to batch release testing for dry medical device manufacturing processes.

References

1.“Bacterial endotoxins—Test methodologies, routine monitoring, and alternatives to batch testing,” ANSI/AAMI ST72 (Arlington, VA: Association for the Advancement of Medical Instrumentation, 2002).
2.DH Stamis, Failure Mode and Effect Analysis: FMEA from Theory to Execution, (Milwaukee, WI: 1995) ASQ Press.
3.C Mitchell and M Williams, “Functional Failure and Effects Analysis of Pharmaceutical Packaging Operations, Part II: Conducting a Successful FFEA,” Pharmaceutical Technology 24, no.8 (2000): 64–68. 
4.J Durkee and J Baker, “C4 Critical Cleaning for Contamination Control: Pyrotechniques about Pyrogens,” A2C2 40 (2001).
5.M Pfeiffer, “Testing Medical Disposables Using the Limulus Amboecyte Lysate (LAL) Test,” Medical Device Technology 37 (1990): 37–51.
6.R Bennett, “Cleanroom Produced Endotoxin-free Plastics,” Insights 15 (2002).
7.“Transfusion and Infusion Assemblies and Similar Medical Devices,” USP NF26 <161> 2049–2050: (Rockville, MD: U.S. Pharmacopieal Convention, 2003).  

Peter S. Lee is a research scientist with Baxter Healthcare Corp. (Deerfield, IL). He is responsible for all pyrogen and bacterial endotoxins testing issues. Bryan Plumlee is a senior quality engineer for process quality of peritoneal dialysis devices. Terri Rymer is an associate research scientist with Baxter. Rob Schwabe is a quality manager with Baxter. Joyce Hansen is Baxter's vice president of sterility assurance.

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