Before any drug or device can be marketed in the United States, it must meet a series of regulations set by the Food and Drug Administration (FDA) that ensure its safety and efficacy. These regulations, part of the Federal Food, Drug and Cosmetic Act, apply to all stages of the development, testing and manufacture of drugs and devices.
In order to make judgements on product safety, the FDA requires pharmaceutical companies to submit sound, traceable analytical data. Good Laboratory Practices (GLP) and current Good Manufacturing Practices (cGMP), part of Chapter 21 of the Code of Federal Regulations (21 CFR), are the result of this requirement. The FDA ensures that GLP and GMP are followed, continually keeping companies current on what are considered to be compliant practices. Companies, in turn, interpret these regulations and develop their own procedures for qualification and validation of equipment, computers and analytical methods.
This backgrounder reviews the essential features of GLP, GMP and 21 CFR Part 11, the FDA regulation that hinges on securing the authenticity and integrity of data.
Good Laboratory Practices A drug or device must be proven safe in nonclinical, or toxicity, studies before it can be tested for safety and efficacy in humans. Good Laboratory Practice (GLP), defined in 21 CFR 58, ensures that a nonclinical study has been conducted properly and that the collected data is valid and of high quality. GLP deals with the organization, process and conditions under which studies are planned, performed, monitored, recorded and reported. Once a nonclinical study has been fully documented, reviewed and approved, testing in humans can begin.
Shortly after the FDA introduced GLP, the Organization for Economic Cooperation and Development (OECD) published a compilation of GLP regulations. OECD member countries have since incorporated GLP into their own legislations. Guidelines on quality assurance for measuring equipment and for calibration have also been published by the International Organization for Standardization (ISO).
Good Manufacturing Practices Once a drug or device successfully completes clinical studies, it can be manufactured and made available to the consumer. Good Manufacturing Practices (GMP), often called current Good Manufacturing Practices (cGMP) to reflect their dynamic nature, regulate the manufacture and distribution of a product. The purpose of GMP is to ensure that safe and effective products are consistently produced and controlled to the quality standards appropriate for their intended use. Compliance with GMP, defined in 21 CFR 210 and 211, requires validation of all critical steps in the manufacturing and distribution processincluding cleaning and testing.
Any drug marketed in the United States must be manufactured in accordance with GMP. Because of this, FDA regulations have set an international benchmark for pharmaceutical manufacturing. In Europe, local GMP regulations exist in many June 2006 1 Good Laboratory Practices (GLP) and Current Good Manufacturing Processes (cGMP) countries and are intended to establish a minimum manufacturing standard for all member states.
GMP are general and represent the minimum requirements around which a company should develop its own specific quality program. Some basic requirements of quality control include:
Adequate facilities, trained personnel and approved procedures for sampling, inspecting, testing and, where appropriate, monitoring environmental conditions of all materials and products Samples of all materials and products, taken using methods approved by quality control Validated test methods Records, made manually and/or by recording instruments, demonstrating completion of required sampling, inspection and testing procedures, thoroughly documenting any deviations Active ingredients that comply with the composition of marketing authorization, are of the required purity and are enclosed within a proper container that is correctly labeled Records of inspection results and formal assessment against specification of all materials and products, including a review and evaluation of relevant production documentation and an assessment of deviations from specified procedures
What is Validation? One of the key requirements of GLP and GMP for analytical laboratories is validation, the evaluation of processes, products or analytical methods to assure that they will consistently produce a product that meets its predetermined specifications and quality attributes. Properly functioning and well-documented instruments, computer hardware and software and validated analytical methods are needed to fulfill regulatory requirements. Validation also includes checking functions related to data integrity, security and traceability. Validation is not a one-time event but ongoing, covering all phases of a product or process.
What must be validated?
Equipment. All computerized equipment used to create, modify, archive, retrieve or distribute critical data for GLP/GMP purposes must be validated. Validation of hardware includes testing the instrument according to documented specifications. If instruments consist of several modules, the entire system should be validated. Validation of computer systems must include the qualification of hardware and software. Analysis method. Validation covers testing significant method characteristics such as sensitivity and reproducibility. June 2006 2 Good Laboratory Practices (GLP) and Current Good Manufacturing Processes (cGMP) Analysis system. The system combines instrument, computer and analytical method. This validation is usually referred to as system suitability testing and tests for documented performance specifications for the specific analysis method. Data. When analyzing samples the data must be validated. The validation process includes documentation and checks for data plausibility, consistency, integrity and traceability. A complete audit trail must be in place, which allows tracing back the final result to the raw data for integrity. Personnel. People should be qualified for their jobs. This includes education, training and/or experience. Reference standards. Reference standards should be checked for purity, identity, concentrations and stability.
21 CFR 11 21 CFR 11 provides rules for the sole use of electronic records in lieu of manual printouts and for the use of electronic rather than handwritten signatures and record archives. With 21 CFR 11, electronic records and signatures can be equivalent to paper records and handwritten signatures. The regulation applies to all industry segments regulated by the FDA, including GLP and GMP.
The primary requirements of 21 CFR Part 11 are: Limited system access to authorized individuals. Use of validated computer systems. Secure retention of electronic records to instantly reconstruct the analysis. User-independent, computer-generated and time-stamped audit trails. Use of secure electronic signatures for closed and open systems. Use of digital signatures for open systems.
Agilent and Compliance The Agilent 1100 Series high-performance liquid chromatography and Agilent 6890/6850 gas chromatography systems provide a reliable, cost-effective path to regulatory compliance and are designed with built-in automated calibration and validation features. In addition, Agilent offers software modules that provide 21 CFR Part 11 support as part of or in conjunction with most of its major analytical software products.