Medical Device Link.

For example, managing corrective and preventive actions (CAPA) and complaints in an electronic environment can help IVD manufacturers realize their business and compliance goals without having to reengineer those business processes and embark on long, complex projects.

21 CFR Parts 820, 809, and 11

21 CFR part 820 sets forth the general provisions and quality system requirements for manufacturing medical devices, including IVD products. It addresses the following requirements: design, document, and purchasing controls; identification and traceability; production and process controls; acceptance activities; nonconforming products; CAPA; labeling and packaging controls; handling, storage, distribution, and installation; records; servicing; and statistical techniques for manufacturing medical devices.

21 CFR part 809 defines IVD products as "those reagents, instruments, and systems intended for use in the diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease or its sequelae." Specifically, 21 CFR part 809 defines the products and product classes that must meet the regulatory requirements for the labeling, manufacturing, production, sale, and distribution of IVD products. All IVD products that fall under the part 809 requirements must also meet the part 820 standards.

IVD manufacturers using electronic records as a system of record for quality data that is governed by part 820 must also meet the requirements of 21 CFR part 11. This regulation defines the criteria for managing electronic records and outlines signature requirements for electronic documentation. FDA planned to release a new draft and proposed rule for part 11 in December 2005. In the interim, the industry-developed good automated manufacturing process guide serves as a first-rate model for IVD manufacturers incorporating a risk-driven, values-based approach to compliance with electronic records.¹ This guide can also serve as a preemptive planning tool for anticipating part 11 changes. While moderately complex, the 21 CFR part 11 requirements are manageable with the right tools.

Manufacturing Best Practices

IVD manufacturers have been slowly embracing the advanced quality techniques that other industries have used for years. This may be due to their focus on compliance and to less-competitive profit margin pressures compared with commoditized industries. Such methods as Six Sigma and lean manufacturing have demonstrated top-line and bottom-line impact by reducing manufacturing cycle times, increasing production yields, and reducing work in progress. IVD manufacturers can realize much untapped potential by implementing advanced quality techniques that use tools such as statistical process control (SPC) and risk management initiatives.

Six Sigma is a business initiative that the automotive, defense, and electronics industries have used for years. Six Sigma's basic premise is that by reducing variations in both products and processes, manufacturers can minimize product defects. Six Sigma methodology is discussed in defective parts per million (DPPM), addressing error rates within one standard deviation (i.e., one sigma) of the mean. For IVD manufacturers, this equates to the number of opportunities for noncompliance. Operating within sigma translates to the consumption of resources (or the cost of compliance) of approximately 65% of sales revenue. Those IVD manufacturers performing at the ideal level (±6 sigma) are operating at 99.9997% compliance (about 3.4 DPPM) and are utilizing less than 10% of sales revenue for the cost of compliance. A not-so-ideal performance (±1 sigma) results in a 30.23% compliance rate. Most companies operate at ±4 sigma, which results in a compliance rate of about 99% (sigma).

Six Sigma relates strongly to an IVD manufacturer's business goals because the cost of noncompliance is high. In general, while those manufacturers spending the most on compliance (about 20–40% of sales revenue) operate within ±3 sigma, others that operate within ±6 sigma spend less than 5% of sales revenue on compliance. Manufacturers in other industries have taken advantage of Six Sigma programs to optimize manufacturing performance so that they can redirect capital resources.

Lean manufacturing is a complementary business initiative that focuses on waste reduction within manufacturing to improve process speed, increase agility, and reduce manufacturing costs. Lean manufacturing initiatives attempt to trim human labor, wasted space, excess inventory, and inefficient processes. The automotive, aerospace, and electronics industries have noted improvements when adopting lean manufacturing programs. Lean manufacturing and Six Sigma (which together is called lean Six Sigma) work synergistically, and can make IVD manufacturers more profitable by optimizing the quality control testing process, reducing cycle times, improving production rates, and reducing risks and costs.

Used in aeronautical manufacturing, SPC is a tool that relies on statistical analysis to improve processes. SPC often functions as a tool to help support a lean Six Sigma initiative. A solid SPC program involves analyzing or measuring a given process, reducing variability within that process, and monitoring and improving the process. Specifically, SPC's goal is to identify variations in processes, determine the normal limits of variation for those processes, and develop practices that ensure minimal variation. IVD manufacturers can integrate SPC into their processes. For example, they can link SPC to continuous dispensing systems and other automated processes. Manufacturers can leverage process analytical technology approaches by tying process variable data to an SPC tool. By doing so, the SPC tool can monitor the process for key constraints that correlate to final product quality, and can alert specified users when a process is trending out of control. Alternatively, an SPC tool can provide closed-loop feedback to appropriate process controllers to bring the process back in control.

Risk management initiatives involve four key elements: analysis, evaluation, control, and postproduction monitoring. Even though many IVD manufacturers have a solid handle on the risk assessment phase of risk management, which involves analyzing the risk and evaluating it within the context of their companies, they encounter difficulties in implementing changes that control risk. In addition, while subsequent post production control measure monitoring is crucial for an effective risk management program, most manufacturers do not have data available to help them monitor such processes and make the necessary changes. As in any manufacturing industry, a rigorous risk management methodology is necessary for IVD manufacturers to achieve the essential goals of quality and performance.

Functionality Needed for True Automation

IVD manufacturers need tools that enable them to access their data and control its quality at any given production point in real time. Such tools form the basis of manufacturing performance management. To do this, manufacturers can use an electronic device history record (DHR) and an electronic batch record (BR), which ensure that good documentation practices are enforced. An electronic DHR or electronic BR must manage comprehensive data for each lot, and must capture required quality data and signatures. They should also ensure that the requirements for each step (whether regarding equipment calibration, operator training, or general processes) are met. For example, when working with assays, kits, and reagents produced in batches, an electronic BR can record every operation, worker, supplier, and test result, and enforce the proper procedures.

Electronic records will help IVD manufacturers with identification and traceability because each lot will have a unique number, and each unit, lot, and batch will be unique. Electronic DHRs and BRs provide functionality for tracking, serialization, quantity reconciliation, and lot and data codes. They also manage acceptance activities, such as receiving, in-process, final acceptances, acceptance records, and acceptance status.

CAPA and complaint management using manual systems are tedious and inefficient processes. Business process automation allows electronic nonconformance tracking and CAPA generation, CAPA action plan tracking, root-cause analysis and workflow management, and corrective action approval and implementation. Escalation rules within the system and automatic notification ensure that operators function according to the company's protocol. An enterprise-class manufacturing execution system (MES) can provide the aforementioned functionality to IVD manufacturers.

What IVD Manufacturers Are Doing Now

Most IVD manufacturers regard compliance and manufacturing best practices as discrete departmental entities within their companies, even though they know that the link between quality and compliance is inextricable. While manufacturers might have an enterprise resource planning (ERP) system, a product life cycle management (PLM) system, an MES, or any combination of these in place, they usually do not use them to their maximum benefit, since the nuances of aligning such systems are not clear to most companies. In reality, although there is some overlap, each of these software solutions has a unique function. For example, ERP focuses on supply-chain activities, while PLM is involved in engineering and product innovation cycles. MES focuses on the actual products and process execution.

Such systems are also interdependent. For example, ERP relies on outside sources for real-time production details and feedback, tracking any details below the order level, and getting results of exceptions to routings and yields. Likewise, PLM depends on other systems when IVD manufacturers need complex specifications (e.g., process specifications and certain acceptance activities), and when they need quality feedback from manufacturing activities and results (as they relate to engineering change requests). MES also relies on other systems to create production plans, and manage orders and documents such as standard operating procedures.

Manufacturing in Overdrive

IVD manufacturers can reduce the cost of compliance and improve the bottom line by synchronizing their ERP, PLM, and MES systems. For example, ERP and MES enhance each other by allowing detailed work-in-progress visibility and traceability, which leads to improved inventory accuracy, planning, and scheduling, and enhanced order visibility. In this way, IVD manufacturers can capitalize on current investments in technology for future productivity and quality benefits.

Similarly, creating an MCP on an MES framework is one way that IVD manufacturers can use technology strategically to meet compliance challenges and attain business goals. Because MES is multidimensional yet works synchronously with the other manufacturing platforms, it elevates manufacturing to the next level. With manufacturing performance management, an IVD manufacturer's management team can implement better management strategies since it sees exceptions in real time and can respond to and remedy problems rapidly. In addition, performance management enables manufacturers to anticipate both process and product deviations, and implement timely preventive actions.

IVD manufacturers can capitalize on the lessons learned in other industries because the fundamental principles are the same: regulatory compliance is a driving force, and data management and control is the key to regulatory compliance and successful major business initiatives, such as SPC, lean Six Sigma, and risk management. While IVD manufacturers have already reported gains in efficiency, cost reductions, and quality and compliance assurance after converting to electronic records, any manufacturer can benefit from leveraging links between compliance and business initiatives.

Conclusion

IVD manufacturers should evaluate their current systems and the many tools available to them for meeting regulatory compliance and business goals. Manufacturers should make sure their software solutions can point to data in real time in all of the various subsystems on which they rely. By using MES as the foundation of an MCP strategy, IVD manufacturers can access the data needed for lean Six Sigma initiatives from the same sources and with the same simplicity for regulatory compliance audits. They will find that 21 CFR parts 809, 820, and 11 can be satisfied while improving business processes, managing SPC initiatives, and reducing the organization's overall risk. By operating preemptively with a consistent current best practices approach, IVD manufacturers will realize what manufacturers in other industries already know: that regulatory compliance is not just necessary business, it is smart business.