Compliant Paperless Calibration for Pharmaceutical Manufacturing
Kevin J. Daubert
Bernard J. Williams
Prime Technologies, Inc
The calibration of instrumentation, devices and equipment, along with many other functions performed during the manufacture of finished pharmaceutical products, are mandated within the FDA’s Code of Federal Regulations Part 211 (Current Good Manufacturing Practice For Finished Pharmaceuticals). These labor-intensive 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 GAMP Good Practice Guide for Calibration Management (through ISPE, International Society for Pharmaceutical Engineering) demands that pharmaceutical manufacturers establish robust calibration systems. Historically these systems have been of varying complexity but have included a significant “Hard Copy” document content. Legacy paperwork and even mixed hybrid systems have included identification and classification of instruments and devices, master instrument lists, calibration schedules, standard operating procedures (SOPs) 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, communication of requirements coupled with accurate and timely reporting of results is a Herculean effort fraught with opportunities for error. The ProCalV5 Compliant Paperless Calibration Solution is the way to successfully navigate this treacherous environment.
An infinite number of measurements are made everyday throughout the world in various industries. The results of these measurements are used to make decisions that could ultimately affect people’s lives, both personally and in the workplace. In many industries, including the pharmaceutical and other life sciences, measurements are taken 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 the production processes.
Calibration is warranted based on good engineering/business practice and standards and regulations that must be adhered to:
Good Engineering/Business Sense – instrumentation will wear and settings drift, either mechanically or because of environmental effects. These conditions can have a negative impact on instrumentation and can ultimately affect the quality of a product.
Regulatory Requirements – Calibration of instrumentation is a requirement outlined in Food & Drug Administration’s Code of Federal Regulations (FDA CFR) Part 211 for Finished Pharmaceuticals.
The main point emphasized through CFR Part 211 is that the failure to comply with its contents, with respect to the manufacture, processing, holding or packing of a drug shall render a drug to be adulterated, which will lead to regulatory action. Sections 211.68 and 211.160 speak specifically to the requirement of calibration for automatic, mechanical and electronic equipment and laboratory controls that are used in the manufacture, processing, packing and holding of a drug product. This section also states that instrumentation on this equipment must be routinely calibrated and checked, governed by an established program (administrative calibration program defined by Standard Operating Procedures). In addition, written records and documentation of such activity must be maintained.
Corporations who 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 guidance that more localized standard operating procedures are derived from. The Paperless ProCalV5 System provides all the necessary tools to effectively respond to these imperatives.
Checks and Balances
Both internal corporate compliance and 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 and in effect to address potential non-compliance issues.
Compliant Calibration System
Investment in The Paperless Compliant ProCalV5 Calibration-Management System is easy to justify, a few of the basic advantages include:
Fewer errors, as 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. The paperless system ensures that everyone who needs to know of a device found out of tolerance or calibration failure is notified in a timely fashion.
The new ProCalV5 system automatically schedules calibration events and notifies the appropriate participants when they’re due.
Technicians are always presented with the correct device calibration specifications and SOPs. The paperless solution performs all necessary calculations and determines event result status. Technicians working in the field utilize Notebook or Tablet PCs and even the latest in Documenting Process Calibrators and return their results electronically to the system, thus increasing the technician’s effectiveness while ensuring strict regulatory compliance and adherence to quality specifications. All calibration data is stored electronically and is easily accessible to all of those who need it.
Better organization is achieved as paper records that are occasionally misplaced, take up a lot of space and are time consuming to retrieve or review are eliminated. The ProCalV5 paperless records are easily stored and retrieved for review or analysis.
The reliable robust paperless system ensures adherence to the planned calibration schedule and procedures, a practice much less expensive than finding out-of-tolerance instruments in the field. Waste is decreased and product quality improved.
Executive management is given the highest level of confidence that the ProCalV5 Paperless System will meet FDA regulations for timely calibrations and thorough, secure documentation.
Classification, Intervals and Limits of Instruments/Devices
An instrument/device is classified based on it’s potential for product impact. For example, a 0-160psi pressure gauge mounted on a utility chase compressed air line may not be as critical to a pharmaceutical process than a flow meter measuring the flow of air in a tablet coating process. This classification is defined and documented in the paperless system, utilizing such terms as critical, non-critical 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 non-critical and utility classifications are used to provide indications of general equipment conditions and for troubleshooting.
Once a classification is assigned to an instrument, frequencies or intervals of calibration must be determined. Initial intervals should be based on the potential failure of the instrument and its impact to product quality, its past history and manufacturer’s recommendations. Other factors should be considered:
1. What is the danger of too long an interval between calibrations?
Adulterated product or safety (e.g. sterility) impact of measured/controlled parameter on product
2. Instrument Reliability and Accuracy.
3. Time from Manufacture to Use?
If this is a relatively short time period, adulterated product could be distributed if improper intervals are set.
The paperless ProCalV5 system easily facilitates the annotation and communication of these critical definitions. Once an instrument is classified and calibration intervals established based on criticality, calibration limits and calibration process tolerances must be set and documented to ensure an effective calibration. The calibration limits are considered the acceptable variation in instrument indication for a given input, and may be documented as the same accuracy limits provided by the instrument manufacturer. The calibration limit may also be documented as a multiple of the stated instrument accuracy, depending on the requirement. The calibration process tolerance is the maximum allowable deviation of an instrument from true value before there is an impact on product, and is utilized for critical instruments/devices. This tolerance is used as an out-of-tolerance trigger, a condition whereby the as-found error during the calibration has exceeded the stated process calibration tolerances. 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 impact on product.
How the Compliant Calibration System is Administered
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 that speaks to how the calibration system is administered, how instruments are calibrated, how technicians/contractors are qualified, maintenance and certification of calibration standards, instrument/device change control history, calibration documentation, records and calibration management systems.
Administrative procedures are the basic requirements of the calibration system that outline many activities including, documentation of calibration activities, review of calibration data/records, notification of out-of-tolerance occurrences to user departments. Quality department review/approval of procedures, instrument change control and other general calibration requirements. 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 the applicable instrument or category of instruments, and provide the technician with guidance and instruction on the calibration steps for that instrument. Important steps to be outlined in these procedures are the documenting of as-found and as-left data, instructions on how adjustments are made, ensuring that accuracy and repeatability checks are performed and specifying the desired number of calibration points to be tested. An instrument/device specific procedure should be created for each instrument type (e.g. pressure indicator, temperature indicator, flowmeter, etc.), and should be manufacturer brand specific.
The process of internal/external calibration technician 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 resume 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 requires to be trained on to perform his/her job effectively, as well as the progress of such training. The Paperless ProCalV5 System provides a complete training management and technician qualification record to ensure that those executing a procedure are qualified to do so.
Calibration standards are likewise managed and documented within the ProCalV5 System. Utilized to ensure that the instruments to be calibrated are tested with a standard of higher accuracy, they must be traceable to NIST or other recognized standards organization. Calibration standards are typically sent out to ANSI/NCSL Z540 and ANSI/ISO 17025 Certified laboratories, are certified and returned with documented evidence of such certification. They 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, but 4:1 is the preferred ratio.
Instrument calibration change control is defined as documentation of the complete instrument history, encompassing the time period from when the instrument was first added to the system to the time the instrument is decommissioned or deleted from the system. The instrument calibration change control form typically includes static instrument description information, classification, calibration interval, calibration limits/tolerances, clarification of test points, and any special instructions or comments to help facilitate proper calibration of the instrument. This important management and technical documentation is now completely managed within the ProCalV5 Paperless System with provisions for approval routing, electronic signature and full audit trail record.
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 reviewed and scrutinized by auditing bodies. Whether for auditing or performance evaluation access to these records are easily facilitated within the ProCalV5 system.
On the other hand, instrument files containing manuals and/or drawings associated with the instrument a technical resource for calibration and troubleshooting. Increasingly available in electronic formats these files are also accessible on-line from the paperless solution to the technician or supervisor
Calibration management solutions used throughout the Pharmaceutical and Life Sciences Industries to manage calibration activities vary greatly. The selection and successful implementation of the Compliant Paperless ProCalV5 Calibration Management System represents an investment in the future and a commitment to quality.
1. Food and Drug Administration, HHS, Code of Federal Regulations, 21CFR210 & 211, Office of the Federal Register, National Archives and Records Administration, April 2002
2. Pennella, C. Robert, Managing the Metrology System, Third Edition, ASQ Quality Press, Milwaukee, Wisconsin, 2004
3. International Society for Pharmaceutical Engineering (ISPE), GAMP Good Practice Guide, Calibration Management, 2002
4. Institute of Validation Technology, Journal of Validation Technology – Conducting Effective Calibrations, 2002
5. Henson, Eldon, Good Manufacturing Practice (GMP) Toolbox, Journal of GXP Compliance, Volume 7, Number 1, 2002
6. Gudesblat, Yefim S., Recommendations for Implementing a Calibration Program, Pharmaceutical Engineering, Volume 23, No. 6, Nov/Dec 2003, pp. 100-114.
7. Gudesblat, Yefim S., Specification and Calibration Requirements for Industrial Scales in Pharmaceutical Applications, Pharmaceutical Engineering, Volume 21, No. 5, pp. 82-89.
8. Barry, Brendan & de Haas, Nigel, Calibration Management – A European Perspective, Pharmaceutical Engineering, Volume 23, No. 6, Nov/Dec 2003, pp. 116-126.
9. International Society for Pharmaceutical Engineering (ISPE) Baseline Pharmaceutical Engineering Guide, Pharmaceutical Engineering Guides for New and Renovated Facilities – Volume 5 Commissioning and Qualification, First Edition, March 2001