2.8: Validation of Processes and Equipment

1. Calibration is a process that compares a known (the “standard” device) against an unknown (the target device in question). During the calibration process, the offset between these two devices is quantified, and the target device is adjusted back into tolerance (if possible). A calibration report usually contains both "as found" and "as left" data. When a micropipette is determined to be out of calibration, it is typically sent to the manufacturer for recalibration.
2. Verification is simply the process of "verifying" that a device is within tolerance (within an acceptable range). Verification usually results in "as found" data. If the device is not within tolerance, it is sent for recalibration.
3. Validation is a detailed process of confirming that the instrument is installed correctly, that it is operating efficiently, and that it is performing without error. Validation in the pharmaceutical industry emerged from problems in the 1960s and 1970s and went together with the QA/QC philosophy that quality is built into the product not tested into the product. The FDA states that quality, safety, and effectiveness are designed and built into the product.

Biomanufacturing Validation

There are three main areas of validation for a biomanufacturing facility. You must validate your process, your equipment, and your methods. The planning of validation occurs throughout the development of the product. The actual validation process is usually performed before large-scale production and marketing of a product begin. Revalidation is required whenever there are changes in raw materials, equipment, processes, or packaging that could affect the performance of the product.

Validation is important both in "traditional" pharmaceutical manufacturing and in the production of medical products using biotechnology methods. FDA's "Guideline on General Principles of Process Validation" (May 1987) is a general guide that applies to most manufacturing situations. There are also specific guidelines for the biotechnology industry, which is found on the FDA website. Validation is a major undertaking that is expensive, time-consuming, and requires extensive planning and knowledge of the system being validated. The advantage of validation is that it helps to assure consistent product quality, greater customer satisfaction, and fewer costly product recalls.

1. Process Validation. Process validation is the method by which companies demonstrate that their activities, procedures, and processes consistently produce a quality result. For example, process validation of a sterilization process might involve extensive testing of the effectiveness of the process under varying conditions, when different materials are sterilized, with different operators, and with various contaminants to make sure that the technique can "clear" the material of the contaminant. During this testing, the effectiveness of contaminant removal would be measured, the temperature and pressure at all locations in the sterilizer would be measured and documented, and any potential difficulties would be identified and recorded.
   Validation demonstrates that the process is effective. Validation and final product testing are recognized as two separate, complementary, and necessary parts of ensuring quality. The requirement for process validation comes from the text of the GMPs, Section 211.100, which states that “there shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess." (fda.gov)

   Test Your Knowledge!

   Read more about Process Validation FDA Guidelines and refer to the PPT presentation.

   1. Discuss the three stages of process validation.
   2. What is the guidance on documentation?
2. Equipment Validation. For a process to proceed correctly, the equipment must be of high quality, must be properly installed, regularly maintained, and properly operated. Equipment must, therefore, be validated to ensure that it will function reliably under all the conditions that may occur during production. Equipment qualification may be and performed separately from process validation, but it is also a requirement for process validation. Equipment Validation is a detailed process of confirming that an instrument is installed correctly, that it is operating efficiently, and that it is performing without error. Equipment Validation is divided into three parts:
   1. Installation Qualification (IQ). First, the equipment item is checked to be sure that it meets its design and purchase specifications and is correctly installed. Installation qualification includes, checking instruction manuals, schematic diagrams, and spare parts lists are present; checking that all components of the device are installed; checking that the materials used in construction were those specified; and making sure that fittings, attachments, cables, plumbing, and wiring are properly connected. IQ is documented proof that the equipment meets the design intention.
   2. Operational Qualification (OQ). After installation, the equipment can be tested to verify that it performs within acceptable limits. For example, an autoclave might be tested to see that it reaches the proper temperature, plus or minus certain limits, in a set period; that it reaches the correct pressure, plus or minus certain limits, etc. The penetration of steam to all parts of the chamber, the pressure achieved at various settings, and so forth, would all be tested in the context of the operational qualification of an autoclave. OQ is documented proof that the equipment performs as specified.
   3. Performance Qualification (PQ). Once all measuring instruments are calibrated, and all equipment is validated, process validation (or qualification) can be performed. The validation of the process will involve assessing the process under all the conditions that can be expected to occur during production. Testing includes checking the process endpoint(s) under these conditions and establishing that the process consistently meets its specifications. PQ also involves challenging the system with unusual circumstances. FDA speaks of the "worst-case" situation(s) that might be encountered during production. PQ is documented proof the equipment or systems operate as intended under challenge conditions.
3. Method Validation. Refers to the method of testing the raw materials, intermediates, and product.

Unplanned Occurrences

After these validation activities have been performed, the collected data is analyzed as described in the validation protocol, and a report is prepared. Successful validation demonstrates that a process is effective and reliable. With careful validation design, planning and implementation problems are easily avoided. Even in the most carefully designed facilities, unplanned occurrences happen. These unexpected events are called deviations, and every company must be prepared to deal with them. Typically, the validation plan will have a form for documenting the deviation. The supervisor and the quality department will review the deviation to determine the plan of action to correct the deviation.