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The challenge is to determine the optimal frequency for preventive maintenance and the optimal frequency and tolerances for calibration readings.
The biotechnology industry has mushroomed over the past decade, with revenues increasing from $8 billion in 1992 to $39 billion in 2003,1 and it shows no signs of slowing down. New therapeutics are entering and pressing through clinical trials. Treatments are emerging from clinical trials ready for marketing and scaling up for commercial production, leading to a growing need for new facilities.
All this growth means that the industry is now facing unique challenges and opportunities in all areas, including managing assets such as instruments and production equipment. Scaling up naturally increases the volume of assets that need to be managed. At the same time, moving into marketing and commercial-scale production means that more and stricter regulations apply, increasing the level of audit scrutiny and the attention that must be paid to compliance. Furthermore, with larger and more sophisticated processes in place, the costs of downtime increase dramatically. To reduce downtime, additional attention is required when scheduling maintenance or calibrations, determining frequency of preventive maintenance, and routing approvals to get a piece of equipment back into production.
Added to the challenges presented by growth is the extraordinary pressure from investors to produce or improve profits within an unusually short timeframe. This pressure translates into getting a new facility up and fully running at lightning speed. In terms of assets, this means selecting (following GAMP 4 guidelines for steps such as User Requirements Specification [URS] development and gap analysis),2 installing, calibrating, and validating each piece of equipment, each instrument, and all related systems and processes. This process not only applies directly to the equipment and instruments, but also to systems used to manage ongoing calibrations, maintenance, and validations of those assets. With strict compliance goals, this means new facilities must be brought on line quickly, correctly (following all regulations), and on budget. These three objectives are rarely achieved simultaneously.
The good news is that new biotech facilities, which do not have legacy computer systems to consider, are uniquely positioned to take advantage of the latest software applications that consolidate asset management. Unlike single-point solutions with add-on "modules," these new systems bring calibration, maintenance, and validation into a single application without forcing any department to compromise how it works in order to collaborate with others. These "regulatory asset management" (RAM) systems reduce duplicated efforts, simplify compliance, and maintain control over the validated state of assets.
Biotech companies are under intense regulatory scrutiny. The management of instruments, equipment, and processes must be accurate and carefully documented. To demonstrate that assets are properly managed, the assets must first be validated, documenting that they are working as required and promised by the vendor. This original validation requires documented evidence that the entire production system results in consistent output. This necessitates performing initial qualifications, including the design, installation, operation, and performance of new instruments, equipment, processes, methods, and systems. Then, over the course of the asset's lifetime, procedures must be in place to keep the asset in that validated state, including regular calibrations and maintenance, and revalidating the asset when something alters its operation, requiring complete approvals before it can be used again.
To achieve their goals, validation specialists use a wide range of systems and tools, including project management systems, document management systems, change control systems, and systems used to manage calibrations and maintenance. Changes to records in any of these systems must pass through a specific approval process before they can be accepted as part of the validated state.
Regulatory agencies expect to see evidence that routine calibrations are being performed to keep instrument readings within tolerances acceptable to the process involved. These calibrations include using an approved standard to take readings at different set points before and after any necessary adjustments are made to determine whether the asset was and is performing within the process tolerance. If the asset is found to be out of calibration, then products and processes affected by that asset need to be discovered and corrected.
Most calibration departments rely on a computerized calibration management system (CCMS) to manage and document calibration activity. These systems are designed to meet the needs of a calibration department, including an instrument-centric approach and features such as measurement data templates and reverse standards traceability.
Just as regulations require that regular calibrations be performed on equipment, regular preventive maintenance also must be performed. This maintenance not only satisfies regulatory requirements for maintaining equipment in its original working order, but also reduces the likelihood that more costly and disruptive emergency maintenance will be required. The challenge is to determine the optimal frequency for preventive maintenance, just as the calibration professional must strive to establish the optimal frequency and tolerances for calibration readings.
Any changes to the asset (i.e., when a similar replacement part is no longer available and new alternatives must be considered), will require change control and completion of review and approval procedures before the asset can return to use. Speedy resolution of change control and like-for-like replacement issues can make a huge difference on the bottom line when dealing with a multimillion dollar piece of equipment or process line. In addition, when operating a maintenance group, managing a pool of people and ensuring that the right person is available for each job is a constant challenge.
To manage all the complications of asset maintenance, many companies use computerized maintenance management systems (CMMS). Activity in CMMS tends to be organized around work orders. If a CMMS was designed for use by biopharmaceutical manufacturers, it can offer a way to manage replacement parts approved for each asset in the validated state.
The Food and Drug Administration and other similar regulatory agencies have started to take a top-down, system-based approach to inspections and audits, called the quality systems inspection technique (QSIT). Instead of looking solely at the end results of processes or focusing on detecting small variations, QSIT focuses on the major elements of the total quality system that are most critical to meeting requirements. As part of implementing this new technique, regulatory agencies are training their inspectors in new areas of focus, including, for example, various disciplines in asset management.
The FDA has grouped Facility and Equipment controls into one of five manufacturing subsystems that make up a complete quality system. According to FDA, the Facilities and Equipment category "includes the measures and activities which provide an appropriate physical environment and resources used in the production of the drugs and drug products."3 See the sidebar for a list of the elements that FDA has grouped under the terms "Facilities" and "Equipment," which include such additional activity as environmental monitoring and IT asset management.
Quality Systems: Facilities and Equipment
Biotech companies are realizing commonalities and interaction between the discipline and management of calibration, maintenance, and validation. For the most part, each group is working with the same set of assets, collecting a lot of the same profile information on the asset: description, ID, manufacturer, applications, etc. There are also similarities in how various groups work with assets: maintenance, calibration, and validation events occur for many assets on a set schedule, with a procedure or collection of procedures to follow for each event, with requirements for documented evidence that the event took place. These commonalities raise questions not only of efficiency, but also compliance concerns when identical data, with possible variations due to errors, are stored in multiple locations.
Taking a uniform approach to these activities and responsibilities is the first step toward achieving a complete and integrated facility and equipment system, on which regulatory audits will pivot.
Biotech companies have explored various options to harmonize systems involved in maintaining the validated state, seeking to achieve improved collaboration and reduce redundancies between departments. For example, many biotech companies have commissioned custom integration between CCMS and CMMS packages to automatically pass information between applications. This allows each department to use software designed to satisfy its specific needs for how it manages its assets. By using one application as the central repository for basic asset information that is then shared with the other application, this approach also eliminates the need for duplicate data entry, reducing inconsistencies. Each system, however, must be implemented and validated separately. Individual version upgrades of the CCMS or CMMS also will not likely be compatible with the original integration, requiring periodic redevelopment work and revalidation of both systems.
Another attempt at harmonization has been to use a single point solution with "add-on modules" (i.e., basic calibration management functionality built into the framework of maintenance management software, or vice versa). However, being built on another system's purposefully built framework, those modules involve significant compromises to efficiency and ease of use for individual departments. For example, a CCMS would lack the sophisticated work order system or inventory management that a CMMS would have. Likewise, a CMMS, driven by work orders, generally requires additional steps and minutes to complete each calibration, not a trivial matter when some companies perform tens of thousands of calibrations per year. When considering this option it is imperative to understand the impact the modules would have on compliance and productivity throughout the departments.
For most companies, however, compromises and costs with existing options have been too great, and as a result, they continue with separate point solutions, encouraging "off-line" collaboration.
The combination of calibration, maintenance, and validation forms the core of regulatory asset management (RAM): the management, scheduling, data collection, and documentation associated with keeping processes, instruments, and equipment in a validated state in regulated production and critical research environments. Systems designed specifically for RAM offer an obvious alternative to biotech companies seeking a best-in-class solution for harmonization of calibration, maintenance, and validation.
In contrast to other solutions, a RAM system truly embraces harmonization; designed to meet the individual needs of calibration, maintenance, and validation groups while also encouraging a holistic and collaborative approach to asset management and the validated state. For example, in a RAM system the scheduling or completion of a performance activity can result in automatic notifications to calibration or validation personnel, to schedule any activity that may result from the maintenance.
A core area in managing regulatory assets is change control. It's in this area that a RAM system really stands out against applications not designed for biopharmaceutical manufacturing, which often apply limited electronic signatures as modular add-ons sitting on top of the main application. In contrast, RAM systems provide an integral audit trail, approval routing, and 21 CFR Part 11 compliant electronic signatures for changes to records throughout the application, from asset and event records to calibration measurement data templates. Best-in-class RAM systems actively expedite an asset's return to a validated and full production state with configurable approval routing that match existing paper-based procedures that vary by asset or record type and sophisticated status management to prevent unapproved records from being used anywhere in production.
The RAM system stores asset information in a single location, eliminating redundant effort and potential inconsistency in entry. Likewise, such a system offers easy access to a piece of equipment's complete history, useful when evaluating and improving reliability and uptime, or making decisions on purchasing similar equipment. These are all benefits that auditors also appreciate seeing, offering a clear systems-based approach.
In addition to bringing all asset information and the approval process under one system, harmonization also reduces the overall costs of ownership, with lower computer hardware and system maintenance costs, fewer vendors, and minimized validation headaches and costs. Once a company has made the transition to a single system for all regulatory asset management, taking advantage of technological advancements is also simplified because there is only a single system to upgrade instead of a compilation of systems that may or may not have integration issues.
Even more so than other regulated life sciences industries, biotech companies are uniquely positioned to implement and benefit from a RAM system. First, with pressure to get a new biotech facility up and running quickly, anything that can reduce the number of projects means becoming operational that much quicker. In this context, one system to implement is better than three or more separate systems.
The biotech industry also tends to have a complex asset environment. Large quantity and a wide variety of instruments and equipment common to biotech companies also add weight to the argument for a single comprehensive approach to asset management. The fact that biotech companies are often under great FDA scrutiny and have tight instrument tolerances also makes a system designed specifically for FDA-regulated industries a wise investment with a swift payback in the form of simpler audits and lower risks of non-compliance.
It is also usually easier to implement the latest best-in-class solutions at new facilities rather than existing facilities. Harmonized systems and processes will be more readily accepted in a new facility than in one where inertia has developed around the old order. With no disparate legacy systems to replace, implementing a unified system also requires less internal conflicts than in existing facilities where there may be reluctance to implement a single system if one of the existing systems has just recently been purchased, implemented, and validated.
With regulatory and business pressures, harmonization within asset management is becoming a necessity within the biotech industry rather than just a best practice or a source of competitive advantage. A RAM system is the optimum solution to achieve harmonization without productivity or compliance compromises.
JAMES ERICKSON is president of Blue Mountain Quality Resources, Inc., 1963 Cato Ave, State College, PA 16801, 800.982.2388, JRErickson@coolblue.com
1. Biotechnology Industry Organization: http://www.bio.org/speeches/pubs/er/statistics.asp
2. Guide for Validation of Automated Systems (GAMP) 4 guidelines, ISPE 2001.
3. FDA Compliance Program Guidance Manual 7356.002, Feb 1, 2002.