Pharmaceutical process validation, qualification and calibration

July 15, 2016

Understanding crucial manufacturing processes in a pharmaceutical facility

A lot has changed in the world of pharmaceutical industries in the last two decades. The cost of research and development (R&D) has gone up, related generics have been launched, and the price of medicine has been increased due to pressure from the U.S. Food and Drug Administration (FDA) and health care systems.

All this has compelled pharmaceutical facilities to make changes in the way they operate — developing creative business solutions, merging with other companies to utilize R&D resources more efficiently, reducing their production workforce and outsourcing good manufacturing practice (GMP) activities to specialized service providers.

This article will discuss the most commonly outsourced GMP processes: validation, qualification and calibration.

Validation, qualification & calibration

Validation is a systematic approach where data is collected and analyzed to confirm that a process will operate within the specified parameters whenever required and that it will produce consistent results within the predetermined specifications. The process verifies if the compliance and quality standards are being met by a product in real time. In a pharmaceutical facility, the validation program establishes that a company is meeting current good manufacturing process (cGMP) guidelines that are set for the industry by concerned regulatory bodies. In short, validation can be considered as documented evidence that the process is meeting the predetermined specifications.

Validation is concerned mainly with processes. When the same approach is applied to a machine or any equipment instead of a process, it is referred to as qualification instead. Qualification is not limited to a validation process, but it is a part of it. It can be further divided into installation qualification (IQ), operation qualification (OQ) or performance qualification (PQ).

Calibration determines if a device or instrument is producing accurate results within the specified limits compared to those produced by a traceable standard over an appropriate range of measurements. Calibration is crucial for justifying qualification and validation. An accredited laboratory can ensure that all the calibration services and activities are performed with qualified instruments.


Validation of computer systems

Every pharmaceutical plant will have an IT system to control, support and document the processes. Computer system validation is a key element because it ensures all the IT applications fulfill their intended purposes. Different phases of design, development, testing and routine of the software being used by the computer system have to be controlled during its life cycle. When the computer system runs accurately, all the information and reports stored in it remain safe.

The documentation is also applied to the computerized system, which manages crucial data that has an impact on the quality of the products. Validation efforts must be focused on important aspects that include risk analysis and an in-depth validation approach. The technical discipline of computer system validation includes all activities that apply appropriate controls through the software development life cycle and procedures required for creating the required documents.

Why calibration is important

Calibration defines measurement parameters such as range, accuracy and precision of an instrument. It is one of the major parts of pharmaceutical manufacturing standards and quality assurance because of these reasons:

With regular use and time, instruments and devices used in the industry will undergo damage, which causes a shift in the measurements. Regulatory inspection will help in tracking the shifts and rectifying through calibration.

When the instrument does not perform within the acceptable range of error, its quality will be greatly affected. Calibration guarantees the quality is not affected by constant errors. This is crucial for processes where the quality of measurement is directly related to the quality of the product.

Certain measurements will be affected by ambient condition such as temperature, pressure and humidity. A change in the surrounding atmospheric conditions will cause a drift in the measurement, and regular calibration will keep this drift within acceptable limits.

Periodic calibration will ensure the measurements and outputs achieved are accurate at all times without affecting the quality of the final product.

How frequently to calibrate

It is important that the instruments are calibrated frequently, but unfortunately, there is no straight answer for how often they should be calibrated. Different instruments have different calibration needs, and they cannot be calibrated every time an instrument is used because of cost.

A good place to start is adhering to the frequency of calibration as suggested by the manufacturer. Follow the timelines recommended by the manufacturer to help eliminate calibration issues.

Other variables that help in determining calibration frequency include:

  • Criticality of the measurement location: Make sure to calibrate the more critical locations more frequently than the less critical ones.
  • Stability history of the instrument: Check how often calibration was required in the past. This will provide a good framework to plan and schedule calibration.
  • Workload and operating conditions: Instruments with too much workload or extreme operating conditions call for more frequent calibration than others.
  • Before extremely important measurements: Calibration is a good idea before a particularly important measurement has to be taken.
  • Sudden unforeseen events: If an electric fault, external conditions that are out of one’s control such as drastic weather and pressure changes, a fall or any other impact occur, conduct a calibration process immediately.
  • Discrepancies suspected in the final product: Any discrepancy or shift from acceptable performance criteria is an indication to calibrate the instrument. Slight variations are normal, but anything that crosses an acceptable limit means calibration is needed immediately.

What happens without calibration

If an instrument is not calibrated for a long time, the following issues can occur:

  • Ambiguous quality: The measurements will become faulty, and discrepancies will be seen, which will reflect on the final product. This will result in questionable quality of the products.
  • Safety issues: In the pharmaceutical industry, the quality of the final product holds extreme importance because it can affect thousands of lives. Non-calibrated instruments will cause wrong measurements of raw materials when producing medicines or instruments of sensitive nature such as thermometers, which can cause serious safety threats to the final users.
  • Misuse of resources: Non-calibrated instruments will waste time and resources, which prove  expensive in the long run.
  • Downtime increases: When the final products show deviance from the required quality, shutting down the process to conduct a complete recalibration is required. This results in increased downtime. Regular calibration will eliminate that and help in detecting warning signs before they affect the final product or cause significant damage.
  • Risk of litigation: When customers realize the product they received does not match up to the expected quality or if they suffer seriously due to the low quality of the pharmaceutical products, they will return the product and ask for a full refund or press legal charges due to the damage caused. This will affect reputation and increase costs. It might even call for a product recall, which is also expensive.

Analytical instrument qualification

Most pharmaceutical industries use digital instruments that have higher accuracy and precision. At the same time, make sure to use the right instrument for the required application. Instrument qualification has become an important part of pharmaceutical cGMP and is a crucial stage to ensure high-quality products. Analytical instrument qualification involves phases that can be categorized into:

  • Design Qualification (DQ) includes activities that define the design elements of the instruments such as functional and operational specifications as well as vendor selection criteria. DQ can be performed by the manufacturers, developers or even the end users.
  • Installation Qualification comprises all activities during the installation of the instrument. IQ checks whether the environment where it is installed is suitable, if the instrument is in accordance with the desired specifications and if the installation procedures have been complied with.
  • Operational Qualification involves collecting document evidence showing that the installed instrument’s performance in the chosen environment will be according to the criteria specified in operational specifications.
  • Performance Qualification requires measuring if the instrument is performing its intended purpose against the activities documented in the PQ stage, which consists of maintenance, change control and calibration.

What to look for in an outsourcing partner

When looking to outsource the activities of validation, qualification and calibration of instruments, it is crucial to choose the right partners. Selecting those who quote the least might be taking a big risk that might cost more in the long run due to production of low-quality products or even posing the threat of potential product recall. When looking for an outsourcing partner, check to see if they have satisfactory answers for the following questions:

  • Are they fully accredited for validation, qualification and calibration by a recognized authority?
  • How strong is their quality management system?
  • Do they meet one’s requirements while containing costs?
  • How trained and qualified are their engineers and technicians?
  • Do they offer and guarantee high quality in their technical competency and documentation skills?
  • Do they have a successful track record and financial stability?
  • Do they own sufficient equipment that is maintained and checked to meet GMP requirements?
  • Does their expertise in IT compliance and validation meet 21 CFR Part 11?
  • How do they respond to fluctuating workloads at their customers’ operations?
  • Do they offer a range of GMP services that will allow the customers to source more than one activity from the same supplier?
  • Do they keep track of all the changing trends, and are they skilled to embrace them?

Choosing the right partner goes a long way. Not only will they provide indispensable assistance, but also they will keep the costs down and maintain GMP standards. Do not rush while choosing an outsourcing partner — take time and finalize the one that guarantees the best.

Edward Simpson is a seasoned calibration and technical engineer working for RS Calibration Inc. Simpson has a knack for finding faults in machines and does not rest until they are rectified to perfection. He lives in Pleasanton, California, and can be contacted at [email protected] for matters related to machines.

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