The calibration of instrumentation, devices, and equipment, along with many other functions performed during the manufacture of finished pharmaceutical products, are mandated within the U.S. Food and Drug Administration’s Title 21, Code of Federal Regulations (FDA 21 CFR), Part 211--”Current good manufacturing practice for finished pharmaceuticals.” These labor-intensive and complex technical functions generate an avalanche of paper that by its very nature is subject to error and delay.
The generally accepted interpretation of the FDA’s compliance imperatives and the principles of calibration described in the Good Practice Guide: Calibration Management (International Society for Pharmaceutical Engineering, 2001) demand that pharmaceutical manufacturers establish robust calibration systems. Historically these systems have been of varying complexity and have included significant “hard copy” document content.
Legacy paperwork and mixed hybrid systems have included identification and classification of instruments and devices, master instrument lists, calibration schedules, standard operating procedures that defined the calibration process, setting tolerances, responses for events, calibration- technician qualifications, effective use of standards, instrument change control, effective documentation, record keeping, and calibration management systems. Management of this mission-critical documentation, and communication of requirements, coupled with accurate and timely reporting of results, is a Herculean effort fraught with opportunities for error. Integrated software that’s compliant with FDA 21 CFR Part 211 is the paperless way to successfully navigate this treacherous environment.
Every day, industries throughout the world perform a huge number of measurements. The results of these measurements are used to make decisions that could affect people’s lives both personally and in the workplace. In many industries, including pharmaceutical manufacturing and other life science businesses, companies take measurements throughout the various stages of the product life cycle to ensure product integrity. The certification and calibration of instrumentation, combined with a robust calibration management system, helps achieve product integrity throughout all production processes.
Calibration is warranted based on good engineering and business practices, and must adhere to standards and regulations in the following ways:
• Good engineering and business sense. Instrumentation wears and settings drift, either mechanically or because of environmental effects. These conditions can have a negative effect on instrumentation and can ultimately affect the quality of a product.
• Regulatory requirements. Instrumentation calibration is a requirement outlined in FDA 21 CFR Part 211.
The main point emphasized by FDA 21 CFR Part 211 is that the failure to comply with its contents, with respect to the manufacture, processing, packing, or holding of a drug, shall render a drug to be adulterated, which will lead to regulatory action. Section 211.68 describes calibration regulations for automatic, mechanical, and electronic equipment, and section 211.160 specifies the general requirements for laboratory controls that are used in the manufacture, processing, packing, or holding of a drug product. Section 211.160 also states that instrumentation on this equipment must be routinely calibrated and checked, and governed by an established program. In addition, companies must maintain written records and documentation of such activity.
Corporations that manufacture pharmaceutical products should have corporate standards that govern how systems are implemented and maintained, including, but not limited to, calibration, maintenance, and equipment qualification. These standards should be used as guidelines from which more localized standard operating procedures are derived. A paperless calibration management system provides all the necessary tools to effectively respond to these imperatives.
Both internal corporate compliance and third-party regulatory bodies conduct audits throughout the pharmaceutical industry to ensure that manufacturers are following their own procedures and to see how they react to issues and deviations to their processes.
A robust calibration system is vital to ensure that when similar audit points are challenged, it can be demonstrated that systems, processes, and procedures are in place to address potential noncompliance issues.
Investment in a paperless system is easy to justify; a few of the basic advantages include:
• Fewer errors occur because planners, managers, and technicians are reliably notified of pending calibration events.
• Calibration obligations cannot be forgotten or overlooked.
• Technicians can no longer perform a calibration without proper documentation.
• The use of unsuitable or out-of-calibration test standards is no longer an option.
• A paperless system ensures that everyone who needs to know of a specific event is notified in a timely fashion if a device is found out of tolerance or if a calibration failure occurs.
A paperless system can automatically schedule calibration events and notify the appropriate participants when they’re due. In addition, technicians are always presented with the correct device- calibration specifications and standard operating procedures. A paperless solution performs all necessary calculations and determines event result status. Technicians working in the field use laptop or tablet computers and the latest in documenting process calibrators, and return their results electronically to the system, increasing the technicians’ effectiveness while ensuring strict regulatory compliance and adherence to quality specifications. All calibration data are stored electronically and are easily accessible to all who need it.
An instrument/device is classified based on its potential to affect a product or products. For example, a 0-160 psi pressure gauge mounted on a utility chase compressed-air line may not be as critical to a pharmaceutical process as a flow meter measuring the flow of air in a tablet-coating process.
This classification is defined and documented in a paperless system using such terms as “critical,” “noncritical,” or “utility.” Characteristically, where process parameters are monitored, controlled, or recorded, and are used to determine product quality, the associated instruments would warrant a critical classification. Most instruments associated with noncritical and utility classifications are used to provide indications of general equipment conditions and for troubleshooting.
Once a classification is assigned to an instrument, users must determine calibration frequencies or intervals. Initial intervals should be based on the potential failure of the instrument and its effect on product quality, its past history, and the recommendations of the manufacturers. Other factors that should also be considered are:
• What is the danger of too long an interval between calibrations? Does a measured and controlled parameter on product have a direct effect on product safety (e.g., sterility)?
• What is the instrument reliability and accuracy?
• What is the time from manufacture to use? If this time is relatively short, adulterated product could be distributed if improper intervals are set.
A paperless system easily facilitates the annotation and communication of these critical definitions. Once an instrument is classified and calibration intervals are established based on criticality, calibration limits and calibration process tolerances must be set and documented to ensure an effective calibration. Calibration limits are the acceptable variation in instrument indication for a given input. The calibration process tolerance is the maximum allowable deviation of an instrument from true value before there is an effect on product and is utilized for critical instruments/devices. This predetermined tolerance is used as an out-of-tolerance trigger. As a result of these out-of- tolerance occurrences, the paperless system automatically communicates the deviation event to the responsible department for investigation of the potential effect on the product.
At the foundation of a compliant calibration system are the instruments that are classified based on criticality, with established frequencies, limits, and tolerances. Another system--administration--must be in place to define how the calibration system is administered, how instruments are calibrated, how technicians or contractors are qualified, how calibration standards are maintained and certified, how instrument and device change-control history is reached, how calibration is documented, and so forth.
Administrative procedures outline many activities, including documentation of calibration activities, review of calibration records, and notification of out-of-tolerance occurrences to user departments. Once again, the paperless calibration system gives the administrator the information and tools needed to accomplish the operational requirements and ensure continued compliance.
Conveniently accessible from the paperless system, instrument/device-specific procedures outline the calibration of specific instruments or category of instruments, and provide the technician with guidance and instruction on the calibration steps. An instrument/device-specific procedure should be created for each instrument type (e.g., pressure indicator, temperature indicator, flow meter, etc.), and should be brand-specific.
The process of an internal/external calibration or contractor qualification should be outlined in a procedure. It is essential to document the qualification, education, training, and experience of the technicians performing calibrations.
Individual training files should be established containing a résumé or curriculum vitae, a qualification assessment memorandum, an approved job description, a job curriculum, a training matrix, and any applicable training certificates or licenses. The job curriculum and training matrix outline the procedures that the individual must be trained on to perform his or her job effectively, as well as the progress of such training. A paperless system should provide a complete training management and technician qualification record to ensure that those executing a specific procedure are qualified to do so.
Calibration standards should likewise be managed and documented. To ensure that the instruments to be calibrated are tested with a standard of higher accuracy, the standards must be traceable to the National Institute of Standards and Technology or to another recognized standards organization. Calibration standards are typically sent out to ANSI/NCSL Z540- and ISO/IEC 17025-accredited laboratories, and are certified and returned with documented evidence of such certification. These documents must be handled with care and properly stored/secured. The accuracy ratio of the standard to the device should be a minimum of 1:1; 4:1 is the preferred ratio.
Other calibration documentation/records include tagging, calibration reports, and instrument files. Instruments are tagged with unique identification numbers, as well as stickers that provide a local indication of calibration status (e.g., calibration pass/fail or out of service). Instrument calibration reports are documented evidence of the calibration, including as-found data, as-left data, standard information, pass/fail indication, and appropriate review signatures.
Instrument history files contain electronic records of calibration reports and calibration change- control forms. These files represent the calibration and repair history of the instrument and serve as the documented evidence of calibration. They are frequently scrutinized by auditing bodies.
On the other hand, instrument files containing manuals or drawings associated with the instrument are a technical resource for calibration and troubleshooting. These files are also accessible online.
Calibration management solutions used throughout the pharmaceutical and life science industries vary greatly. The selection and successful implementation of a compliant paperless system represents an investment in the future and a commitment to quality.
Bernard J. Williams, M.E., is director of sales engineering and consulting for Prime Technologies Inc. Williams is an executive with more than 30 years of engineering and management experience with leading-edge technology companies. He has worked in such diverse fields as power generation, holography, analytical chemical systems, and process automation. For the last 10 years, Williams has worked with Prime Technologies Inc. as the senior technology consultant and contributor to the development of its ProCalV5 computerized calibration and maintenance management solution.