As analytical chemists, we spend considerable time thinking about and working with basic scientific principles combined with the technology and products that allow us to solve our analytical problems. However, it is essential for success of any method and for the long-term success of a laboratory operation that our science and technology are supported by a quality system that ensures continuing achievement of our operational goals. We therefore present a triangle concept for analytical success: One side of the triangle shows our need to understand fundamental scientific concepts. A second, and equally sized side, is the ability to apply current technology, applications, software, and techniques in the laboratory. Finally, the base of this equilateral triangle is the quality system. If any one side of the triangle is given inadequate attention or, worse yet, is missing then we cannot hope to achieve overall success for the laboratory operation.
Figure 1: A successful analytical laboratory operation must be built on three elements: understanding of the basic science, an ability to apply current technology and applications, and a quality system that ensures continued compliance of the operation with pre-established criteria for success.
Previous technical articles discussed specific science and technology issues related to the process of method development for LC/MS. These provide inputs to two sides of our triangle from Figure 1. However, the base of the triangle, the Quality System, must also be addressed by answering such questions as:
- What are the analytical goals of this method in terms of reproducibility, throughput, ruggedness, and portability?
- What instruments is the method targeted for and how do we know those instruments can reliably perform this method now and in the future?
- What are the training requirements for the analysts who will carry out this method?
- What criteria must be applied to determine the suitability of columns, reagents, chemicals, and accessories for this method?
- How do we determine, on an ongoing basis, if the method is performing as expected and required?
The answers to these questions require an understanding of concepts such as validation and compliance; qualification of the instruments (IQ, OQ, PQ), prior to their selection and use; and ultimately the development of a set of system suitability requirements. The semantics and terminology can be confusing to laboratory personnel as well as management. It is critical for those working in regulated industries such as pharmaceutical development or environmental testing to understand these terms and the processes associated with them. However, analysts in other work environments will also benefit from applying these concepts when developing methods.
Quality: The use of the term “quality” is rather ubiquitous and pervades across the industries. Although this term is applied quite widely, it can serve a meaningful and practical purpose only when one descends down to the next level of depth by addressing Critical Quality Attributes (CQAs). CQAs can be ascribed to a process, method, or system which can be measured in some clever or unique way and which can be maintained at a desirable or acceptable level by adherence to predetermined specifications or acceptance criteria. Hence a simple definition of Quality may be: Quality is conformance to a pre-established set of requirements and/or specifications or in more generic way meeting customer satisfaction. Various Quality Control (QC) activities and measures which may be circumscribed by a properly designed, fully encompassing, and robust Quality System with proper oversight by Quality Assurance (QA) will help the management of the organization to achieve and maintain quality when properly implemented.
Qualification of Instruments & Systems: Refers to the ability of a particular instrument/system to operate and perform while meeting the acceptance criteria of their functional, operational, and other capabilities and desired outputs. When considering an analytical system which has hardware, hydraulic, mechanical, electronic and software components, the process of qualification needs to consider and test each such component including the data processing and data handling capabilities of the entire system. The qualification activities are normally separated and categorized into four stages:
- Design Qualification (DQ): Defines the functional and operational specifications; carried out by the manufacturer during design, development, and production of the instrument.
- Installation Qualification (IQ): Establishes that the instrument is received as designed and specified and that it is properly installed; carried out jointly by the manufacturer and end user at the user’s site.
- Operational Qualification (OQ): Demonstrates that the instrument will function according to the operational specifications; carried out by the analysts in the specific environment in which the instrument is used.
- Performance Qualification (PQ): Demonstrates that an instrument will consistently function according to specifications appropriate to its routine use; carried out by the analysts as on-going preventative maintenance and system suitability tests.
Method Validation: Every method needs to go through a systematic process of validation. Apart from becoming a requirement in the regulated environment, there is a scientific need to validate the method prior to its use. However, it is important to understand the overall purpose of such determinations. An excellent definition can be found in the U.S. Food and Drug Administration (FDA) guidelines which define validation in a generic way as “…establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specification. ”
Methods development, optimization and the subsequent stage of validation is an iterative, sequential process which aims at establishing the CQAs of the method (often called validation parameters or method performance characteristics), in a systematic manner with a risk-based strategy and a goal to instill quality in the method from the outset by design. Method validation can also be be viewed as the exploration, investigation, and establishment of the extent of different kinds of errors associated with a particular analytical measurement process, in a generic sense.
